KR20120064656A - trans?splicing group I ribozyme specific for Kras G12V RNA - Google Patents

Abstract

The present invention relates to a trans-splicing group I ribozyme capable of specifically recognizing a short nucleotide variant transcript, and more particularly, specifically recognizing the short nucleotide variant Ras RNA of the 12th codon of the Kras gene. To trans-splicing group I ribozymes which may be substituted by
Since ribozyme of the present invention specifically recognizes a single nucleotide variant gene transcript from a normal gene transcript, it is possible to specifically treat and diagnose cancer cells expressing a mutant transcript using such ribozyme. .

Description

Trans-splicing group I ribozyme specific for Kras G12V RNA that can specifically recognize Krás G12V RNA

The present invention relates to a trans-splicing group I ribozyme capable of specifically recognizing a Kras single base variant transcript.

Radiation therapy and chemotherapy, which are currently mainly used as chemotherapy, are ineffective for patients who are resistant to these methods, and have limitations that can cause side effects even in normal cells. Therefore, for a more specific cancer treatment, there is a need for a method of inducing specific cell death only in cancer cells.

Ras protein is a small GTPase protein that regulates cell growth, proliferation and differentiation. It is evolutionarily highly conserved and expresses different amounts for each tissue.

These ras isoforms, H-ras, N-ras, and K-ras, function differently with the same activator and effector by different positions (John F. Hancock. RAS proteins) :. different signals from diffrent locations Nature Molecular Cell Biology 4; 373-384 ( 2003 )). RAS isoforms have a similarity of about 85% and are not essential for normal development through one or simultaneous knockout experiments of H-ras and N-ras.

However, it has been reported that K-ras is an essential protein that becomes embryonic lethal (Johnson, L. et al.) al ., K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev . 11; 2468-2481 ( 1997 )).

The activity of RAS protein in normal cells is regulated by the binding ratio of GTP and GDP (Campbell, SL et al ., Increasing complexity of Ras signaling. Oncogene 17;1395-1413 ( 1998 )). The active state of RAS protein is determined by the binding of GTP or GDP. RAS-GTP is active and RAS-GDP is inactive, inducing continuous phosphorylation of lower-level proteins such as RAF, PI3K, RALGDS, and PLCε. Thus, it acts as a "molecular switch" that transmits signals from the outside (Fabbro, D. et al ., Protein tyrosine kinase inhibitors: new treatment modalities Curr . Opin. Pharmacol . 2; 374-381 ( 2002 )) .

Inactive RAS can be activated by releasing GDP by guanine nucleotide exchange factors (GEFs) and allowing GTP binding. Termination of Ras signaling is inactivated by activating the endogenous GTPase of RAS by GAPs (GTPase activating proteins) and converting GTP to GDP (John F. Hancock. RAS proteins: different signals from diffrent locations. Nature locations. Molecular Cell Biology 4 ; 373-384 ( 2003 )).

The expression of RAS is tissue-specific, and many RAS mutations have been found in cancer of each tissue. In the case of Kras, it is highly expressed in colon, thymus and lung. In colon, pancreatic, and lung cancer, the G12V single-base mutation of Kras decreases the affinity and activity of GAP due to structural changes in the RAS protein. Therefore, the GTPase activity of RAS is reduced, so that RAS continuously maintains the activity of the protein (Fabbro, D. et al. al ., P A. Protein tyrosine kinase inhibitors: new treatment modalities, Curr . Opin . Pharmacol . 2; 374-381 ( 2002 ); Fahd Al-Mulla et al ., Structural differences between valine-12 and aspartate-12 ras protein may modify carcinoma aggression. J. Pathol 18; 433-438 ( 1999 )).

Looking at the relationship between the Kras gene and human cancer, mutations in the K-ras gene were found in 33% of NSCLC (Non small cell carcinoma), 44% of colon cancer and 90% of pancreatic cancer. In other ras types, mutations in N-ras are found in melanoma (13%), liver cancer (30%), and plasmatic leukemia (30%), while H-ras is found in bladder (10%) and kidney cancer ( 10%) (Mu DQ et al ., Xualues of mutations of K-ras oncogene at codon 12 in detection of pancreatic cancer. World J Gastroenterol . 10(4); 471-5. ( 2004 )).

Among them, lung cancer, in particular, has no pain, so the diagnosis of onset is delayed, and more than 85% of lung cancers are known to die. In fact, more people die of lung cancer than colon, breast and prostate cancer.

Lung cancer is largely divided into Non Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) according to the microscopic shape of cancer cells. Small cell lung cancer accounts for 15-30%, and other lung cancers account for 10%.

The non-small cell lung cancer is classified into squamous cell carcinoma, adenocarcinoma, and large cell carcinoma (Minamoto T., Mai M. and Ronai Z. K-ras mutation: early detection in). molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers a review. Cancer Detect Prev , 24(1); 1-12. ( 2004 )).

The squamous cell carcinoma is the most common form of lung cancer and occurs in the center of the lung, and is known to be the most common form of lung cancer in men and is most related to smoking. In addition, adenocarcinoma is mainly found around the lungs and metastases to the liver, brain, bones, etc. Lastly, large cell carcinoma accounts for 4-10% of all lung cancers, mainly occurs around the lungs, and cancer cells proliferate rapidly and metastasize tends to be fast.

The small cell lung cancer mainly occurs first in the airways. It is usually produced along the surface or line of the trachea, most (80%) occurring in the middle of the lungs and the rest (20%) occurring in the periphery. Overall, the degree of malignancy is strong, and there is a tendency for early metastasis through the lymphatic system or blood circulation. Small cell lung cancer cancer cells usually grow in a small, round shape, which is also called oat cell after its shape.

As the other cancer, bronchioloalveoiar carcinoma is a slow-growing cancer cell, often found in older people, with varying degrees of progression. In addition, giant cell carcinoma, which occurs in less than 1% of all lung cancers, appears largely in the periphery, and progresses rapidly because of severe malignancies.

Among them, 46% of squamous cell carcinomas and 44% of adenocarcinomas are caused by mutations in K-ras, of which 40% are known as single-base mutations in K-ras (Minamoto T., Mai M., and Ronai Z. . K-ras mutation:. early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers Cancer Detect Prev . 24(1); 1-12. ( 2000 )).

Kras is a high-level protein involved in the signaling of cell growth, division, and differentiation within a cell. Among Kras mutations, codons 12, 13 and 61 are known as hot spots. In particular, mutations in the 12th, 13th, and 61st codons of Kras cause structural changes in the region encoding the domain involved in the hydrolysis of GTP, inducing the continuous growth of the cell and developing into a cancer cell.

Meanwhile, Tetrahmena A group I intron ribozyme from thermophila targets and attaches the exon RNA attached to its 3'end in the test tube to the 5'exon. -It has been reported that it may cause a splicing reaction (Been, M. and Cech, T. One binding site determines sequence specificity of Tetrahymena pre-rRNA self-splicing, trans-splicing, and RNA enzyme activity. Cell 47 ; 207 -216. ( 1986 )). It has been found that these ribozymes can also occur in mammalian cells (Jones, JT, Lee, SW, and Sullenger, BA Tagging ribozyme reaction sites to follow trans-splicing in mammalian cells. Nat . Med . 2; 643-648. ( 1996);. Lee, SW Effects of substrate RNA structure on the trans-splicing reaction by group I intron of Tetrahymena thermophila Korean Journal of Microbiology 35; 211-217. ( 1999 )).

This suggests that the transcriptome of genes related to several genetic diseases can be corrected through the trans-splicing reaction of group I ribozyme. precursor) cells in β-globin gene transcripts can be converted into anti-sickling, γ-globin gene transcripts by trans-splicing ribozymes (Lan, N., Howrey). ., RP, Lee, SW, Howrey, RP, Lee, SW, Howrey, RP, Smith, CA, and Sullenger, BA ribozyme-Mediated Repair of Sickle β-globin mRNAs in Erythrocyte Precursors Science 280;. 1593-1596 (1998 );.. Lan, N., Rooney, BL, Lee, SW, Howrey, RP, Smith, CA, and Sullenger, BA Enhancing RNA repair efficiency by combining trans-splicing ribozymes that recognize different accessible sites on a target RNA Mol Ther . 2; 245-255. ( 2000 )).

In addition, when ribozymes that recognize different sites are reacted together, the trans-splicing reaction is further increased (Lan, N., Rooney, BL, Lee, SW, Howrey, RP, Smith, CA, and Sullenger, . BA Enhancing RNA repair efficiency by combining trans-splicing ribozymes that recognize different accessible sites on a target RNA Mol Ther 2;... 245-255 (2000)).

In addition, it has been reported that trans-splicing ribozyme can also modify the myotonic dystrophy protein kinase gene transcript in mammalian cells (Phylactou, LA, Darrah, C. and Wood, MAJ. Ribozyme- ... mediated trans-splicing of a trinucleotide repeat Nat Genet 18;. 378-381 (1998)). The mutant skeletal muscle chloride channel RNA that causes myotonic congenita could also be corrected in terms of function (Rogers, CS, Vanoye, CG, Sullenger, BA, and George, Jr., AL Functional repair of a mutant chloride channel using a trans-splicing ribozyme. J. Clin . Invest . 110; 1783-1798. ( 2002 )).

In order to increase the specificity and activity of ribozyme, ribozyme with IGS modified internal guide sequence (IGS), a target RNA recognition site, targets cucumber mosaic virus RNA, a plant pathogen, to target cytotoxins. When designed to be trans-spliced, it has been shown that only cells expressing viral RNA in yeast can specifically interfere with their growth (Ayre, BG, Kohler, U., Goodman, HM, and Haseloff, J. Design of highly specific cytotoxins by using trans-splicing ribozymes. Proc . Natl . Acad . Sci . 96; 3507-3512. ( 1999 )).

As another example, when the internal guide sequence is modified as above and a ribozyme capable of trans-splicing by targeting a mutant p53 RNA is expressed in cancer cells associated with a deficient p53 in the human body, the mutant p53 transcript is effectively corrected. Normal p53 activity was induced (Watanabe, T., and Sullenger, BA Induction of wild-type p53 activity in human cancer cells by ribozymes that repair mutant p53 transcripts. Proc . Natl . Acad . Sci . 97; 8490-8494. ( 2000 )). These studies suggest that trans-splicing ribozymes can correct mutant gene RNA to normal RNA.

In addition, recently developed a ribozyme that specifically recognizes the IRES RNA of the hepatitis C virus, and by replacing HCV IRES RNA with a cell death-causing RNA by this ribozyme, only cells expressing the target RNA can selectively induce apoptosis. was (Ryu, KJ, Kim, JH , and Lee, SW Ribozyme-mediated selective induction of new gene activity in hepatitis C virus internal ribosome entry site-expressing cells by targeted trans-splicing Mol Ther 7;... 386-395 ( 2003 )).

Thus, these results suggest that a cancer-specific gene transcript can be targeted by trans-splicing ribozymes and then reprogrammed to replace the RNA with another gene transcript.

Until now, many studies have been conducted targeting ras in cancer therapy, and attempts such as antisense oligonucleotides to block the expression of RAS protein or attempts to block membrane localization of RAS using inhibitors have been reported. In addition, attempts have been made to use inhibitors of sub-step interacting proteins to block the function of ras.

However, these attempts did not specifically remove or inhibit a specific RAS target or mutated RAS, and thus had problems affecting normal cells. In addition, cancer could not be cured by simply removing and inhibiting a portion of the expressed RAS. There is a problem that it does not. In addition, RNA interference of Kras G12V using siRNA, which has been studied recently, is specific for mutant Kras, but is not suitable in that it interferes with off-target effects and transmutation reactions.

Therefore, the present inventors consider the above points, Tetrahymena intensive research efforts result for the gene therapy method that let thermophila group I intron Lee, trans whether a single base mutation in the 12th codon of Kras selectively - Fly Let's develop that Li Xing, and these ribozymes are in vitro and in In vivo , the mutant Kras transcript can be recognized and cut, and the 3'exon of ribozyme can be linked to the down-steam of the target site. At this time, cancer cells can be selectively replaced by replacing the exon of the ribozyme with a therapeutic gene or a reporter gene. It was confirmed that it can be treated or diagnosed with, and the present invention was completed based on this.

Accordingly, an object of the present invention is to provide a trans-splicing group I ribozyme capable of specifically recognizing and replacing a single base mutant Ras RNA and a use thereof.

In order to achieve the above object, the present invention

A trans-splicing group I ribozyme capable of specifically recognizing and substituting a single base variant Ras RNA and a use thereof are provided.

In addition, the present invention provides a vector expressing the above-described ribozyme and uses thereof.

At this time, the ribozyme specifically targets Kras G12V RNA, and the 3'exon may contain a therapeutic gene or a reporter gene.

The ribozyme of the present invention specifically recognizes a single-base mutated gene transcript from a normal gene transcript, and thus cancer cells expressing a mutant transcript can be specifically treated and diagnosed using the ribozyme. .

1 is a schematic diagram showing a trans-splicing ribozyme-mediated RNA reprogramming.
Figure 2 shows the secondary structure of Kras RNA [arrow: Kras 12th codon].
Figure 3 shows a schematic diagram of Kras RNA and specificity trans-splicing ribozyme.
4 shows in vitro It shows the structure of Kras 12V produced from the Kras wild type through mutation formation.
5 shows in It shows the analysis of Kras G12V trans-splicing products of KRib1 and KRib2 in vitro [A: RT-PCR analysis, BC: sequencing (B: KRib1, C: KRib2)].
6 shows a trans-splicing ribozyme with increased specificity and efficiency by modifying the P1/P10 helix and the antisense site [A. Schematic diagram of the modified ribozyme, arrows: trans-splicing junction; B. Modified KRib1, structure of KRib2].
7 is in It shows the results of trans-splicing efficiency and specificity analysis of the modified ribozyme in vitro [AB: RT-PCR analysis of trans-conjugated products, CD: sequencing of trans-conjugated RT-PCR products (C: AS300KRib1, D: AS100KRib2)].
Figure 8 shows the results of a reporter assay for confirming the selective induction of transgenes by trans-splicing ribozyme [A: construct for reporter analysis in 293 cells, B: Kras (wild type or 12V) RNA and labeling Transfection of ribozyme (KRib1 set / KRib2 set) containing Nilla luciferase].
9 shows the results of RT-PCR analysis to confirm the selective expression of the transgene by trans-splicing ribozyme [A: construct for reporter analysis in 293 cells, B: Kras (wild or 12V) RNA RT-PCR of contained ribozyme (KRib1 set / KRib2 set); W: wild-type Kras, 12V: Kras G12V, IGS: internal guide sequence, D) KRib: inactive ribozyme].
Figure 10 shows the cell degeneration by TK gene induction in the cell line SW480 endogenously expressing Kras G12V [A: construct for TK analysis in SW480 cells, B: transfection of AS100KRib2-TK containing GFP gene]
Figure 11 shows the generation of recombinant adenovirus by homologous recombination in bacteria [A: schematic diagram of a recombinant adenovirus delivery system, B: construct of adenovirus ribozyme recombination].
12 shows the analysis of recombinant Ad-AS300KRib1-TK [A. Virus genome confirmation by PCR before virus purification, B: Ad-AS300KRib1-TK expression confirmation by RT-PCR before virus purification in Kras G12V mutated SW480; TK: Thymidine Kinase, LITR: Left Inverted Terminal Repeat].
13 shows the analysis of recombinant Ad-AS100KRib2-TK [A. Virus genome confirmation by PCR before virus purification, B: Ad-AS100KRib2-TK expression confirmation by RT-PCR before virus purification in Kras G12V mutated SW480; TK: Thymidine Kinase, LITR: Left Inverted Terminal Repeat].
14 shows the analysis of recombinant Ad-AS100KRib2-LacZ [A. Virus genome confirmation by PCR before virus purification, B: Ad-AS100KRib2-LacZ expression confirmation by RT-PCR before virus purification in Kras G12V mutated SW480; LITR: Left Inverted Terminal Repeat].
15 shows the analysis of trans-conjugated RNA products using an adenovirus delivery system in Kras G12V mutated cancer cells SW480.
Figure 16 is an analysis of the cell viability of specific trans-splicing ribozyme by the adenovirus delivery system in tumor cell lines [A: Cell viability MTS analysis in SW480 (KrasG12V) ([left panel: MOI dependent / 100uM GCV) , right panel GCV dose dependent / virus 150M.OI), B: Cell viability MTS analysis in CAPAN-1 (KrasG12V) (MOI dependent / 100uM GCV), C: cell viability MTS analysis in HT-29 (wild Kras) (left panel: MOI dependent / 100uM GCV, right panel GCV dose dependent / virus 150M.OI)].
Figure 17 shows the analysis of adenovirus-encoding Kras G12V-specific ribozyme in a xenograft mouse model [A: Intraperitoneal CAPAN-1 (Kras G12V) tumor model (n=6 or 7) in Ad-ribozyme Showed efficient and specific tumor regression by, B: no tumor regression by Ad-ribozyme in the subcutaneous HT-29 (wild type Kras) tumor model (n=7)].

Hereinafter, the present invention will be described in more detail as follows.

The ribozyme of the present invention is a trans-sense capable of specifically recognizing and replacing Ras RNA, a single base mutation of the Ras gene that can diagnose cancer progression, especially a single base mutation of the 12th codon of the Kras gene. This is Flyshing Group I Ribozyme.

1 is a schematic diagram showing a trans-splicing ribozyme-mediated RNA reprogramming.

Referring to FIG. 1, the ribozyme of the present invention recognizes and cuts the KRas transcript in which the 12th codon is mutated from GGT to GTT among the mutations of Kras, the oncogene causing carcinogenesis, and downstream of the target site ( down-steam) to the 3'exon of ribozyme. At this time, the 3'exon of ribozyme contains a therapeutic gene or a reporter gene, thereby correcting the mutant KRas transcript and selectively inducing or diagnosing cell death of only cancer cells, thereby treating or diagnosing.

Group I introns recognize targets with six internal guide sequences (IGS), and at this time, a G?U wobble base pair at the 5'end is essential. Accordingly, the ribozyme of the present invention has'GCAGCU' as an internal guide sequence to form a G?U wobble base pair with T, which is the 35th nt in targeting K-ras 12V, where the 12th codon is mutated to GTT, or 36 The inner guide nucleotide sequence was'GACAGC' so as to form a nt T and G?U wobble base pair.

Here, the therapeutic gene refers to a nucleotide sequence that is expressed in cancer cells and exhibits a therapeutic effect. For example, a drug sensitivity gene, apoptosis gene, a cell proliferation inhibitory gene, a cytotoxic gene, a tumor suppressor gene, an antigenic gene, an angiogenesis gene, a cytokine gene, and the like are included, but are not limited thereto.

The drug-sensitizing gene is a gene for an enzyme that converts a non-toxic prodrug into a toxic substance, and is also called a suicide gene because the transfected cell dies. That is, when a non-toxic precursor is systemically administered to normal cells, the precursor is converted into a toxic metabolite only in cancer cells, thereby changing the sensitivity to drugs, thereby destroying cancer cells. Representatively, HSV-tk (Herpes simplex virus-thymidine kinase) gene, ganciclovir, E. coli cytosine deaminase (CD) gene, and 5-fluorocytosine (5-FC) ) Is possible.

The apoptotic gene refers to a nucleotide sequence that is expressed and induces programmed cell death. Apoptosis genes known to those skilled in the art, encoding p53, adenovirus E3-11.6K (derived from Ad2 and Ad5) or adenovirus E3-10.5K (derived from Ad), adenovirus E4 gene, p53 pathway gene and caspase. It includes genes that do.

The cytostatic gene refers to a nucleotide sequence that is expressed in a cell to stop the cell cycle during the cell cycle. Representatively, p21, retinoblastoma gene, E2F-Rb fusion protein gene, genes encoding cyclin-dependent kinase inhibitors (e.g., p16, p15, p18 and p19), growth arrest specific homeobox , GAX) gene (International Patent Application Publication No. WO 97/16459 and WO 96/30385).

The cytotoxic gene refers to a nucleotide sequence that is expressed in cells and exhibits a toxic effect. For example, there is a nucleotide sequence encoding Pseudomonas exotoxin, lysine toxin, diphtheria toxin, and the like.

The tumor suppressor gene refers to a nucleotide sequence that can be expressed in a target cell to suppress a tumor phenotype or induce apoptosis. Typically, tumor necrosis factor-a (TNF-a), p53 gene, APC gene, DPC-4/Smad4 gene, BRCA-1 gene, BRCA-2 gene, WT-1 gene, retinoblastoma gene (Lee et al ., Nature , 329,642, 1987 ), MMAC-1 gene, adenomatous polyposis coil protein (Albertsen et al . U.S. Patent Publication No. 5,783,666), a defective colon tumor (DCC) gene, MMSC-2 gene, NF-1 gene, a nasopharyngeal tumor suppressor gene located on chromosome 3p21.3 (Cheng et al . Proc. Nat. Acad . Sci ., 95,3042-3047, 1998), MTS1 gene, CDK4 gene, NF-1 gene, NF-2 gene and VHL gene.

The antigenic gene refers to a nucleotide sequence that is expressed in a target cell to produce a cell surface antigenic protein that can be recognized by the immune system. Examples of antigenic genes known to those skilled in the art include carcinoembryonic antigen (CEA) and p53 (Levine, A., International Patent Application Publication No. WO 94/02167).

The cytokine gene refers to a nucleotide sequence that is expressed in a cell to generate a cytokine. Representatively, GM-CSF, interleukin (IL-1, IL-2, IL-4, IL-12, IL-10, IL-19, IL-20), interferon α, β, γ (interferon α-2β), and Fusions such as interferon α-2α-1, and the like.

The anti-angiogenic gene refers to a nucleotide sequence that is expressed and releases an anti-angiogenic factor to the outside of the cell. Examples include angiostatin, an inhibitor of vascular endothelial growth factor (VEGF), and endostatin.

In addition, in the present invention, a reporter gene may be conjugated to a down-steam site of a target site through the above-described ribozyme activity. Since the reporter gene conjugated in this way is expressed as a reporter protein, cancer cells can be diagnosed by measuring the activity or amount of the expressed reporter protein.

At this time, the reporter gene may be used as known in the field to which the present invention belongs, and preferably LacZ, chloramphenicol acetyl transferase (CAT), Renila luciferase, firefly luciferase. , Red fluorescent protein (RFP), green fluorescent protein (GFP), secreted placental alkaline phosphatase (SEAP) or HSV-tk (Herpes simplex virus-thymidine kinase). Among them, it is preferable to use LacZ from the viewpoint of convenience and sensitivity of the activity assay.

The activity of these reporter proteins can be measured using methods known to those of skill in the art as follows:

Firefly luciferase (de Wet J. et al. al ., Mol. Cell Biol ., 7, 725-737, 1987), Renilla luciferase (Lorenz WW et al ., PNAS 88, 4438-42, 1991)), chloramphenicol acetyltransferase (Gorman C. et al.) al ., Mol. Cell Biol ., 2, 1044-1051, 1982), LacZ (Hall CV et al ., J. Mol. Appl . Genet ., 2,101-109, 1983), human growth hormone (Selden R. et al .., Mol. Cell Biol ., 6, 3173-3179, 1986), green fluorescent protein (Chalfie M. et al ., Scienc e, 263, 802-805, 1994) and secretory placental alkaline phosphatase (Berger, J. et. al ., Gene , 66, 1-10, 1988). In addition, when thymidine kinase is used as a reporter protein, a positron emission tomography (PET) imaging method may be used.

According to Example 1 of the present invention, the twelfth codon of the mutation of Kras, an oncogene that causes carcinogenesis, targets Kras mutated from GGT to GTT, and is KRib1, KRib2 trans-splicing ribozyme. Was produced.

At this time, in targeting K-ras 12V, where the 12th codon has been mutated to GTT, KRib1 designed to form a T and G?U wobble base pair, which is the 35th nt, and KRib2 designed to form a T and G?U wobble base pair, which is the 36th nt. Was produced.

According to Example 2 of the present invention, the prepared ribozyme in A trans-splicing reaction experiment was performed in vitro, and it was confirmed that the ribozymes KRib1 and KRib2 targeting Kras G12V specifically recognized and cleaved Kras G12V and linked the 3'exon of the ribozyme to the correct target site. there was.

According to Example 3 of the present invention, a ribozyme having only IGS and a modified ribozyme in which P1, P10, and AS (antisense) structures were added to increase efficiency were prepared, and in vitro The trans-splicing reaction was carried out. As a result, it was confirmed that ribozyme with P1, P10, and AS was excellent in terms of specificity and efficiency.

According to Example 4 of the present invention, reporter analysis was performed using a reporter gene to determine whether expression of a trans-conjugation product, that is, a transgene, was induced in cells, and as a result, the expression of luciferase in the cell line was confirmed, and it was also seen in the cell. It was found that the ribozyme of the invention specifically causes trans-splicing, and the expression of the transgene is induced.

In addition, to see trans-splicing at the RNA level, 293 cells were co-transfected with ribozymes and Kras (G12V, wild type) RNA, followed by RT-PCR. As a result, AS300KRib1-F.luc in set 1 and AS100KRib2-F.luc in set 2 in vitro Consistent with performing the trans-splicing analysis, a band of the size expected to be a trans-splicing band came out. In order to confirm that this band is not a non-specific band but a trans-splicing product, sequencing was performed to confirm that trans-splicing occurred accurately at the target site of Kras G12V.

According to Example 5 of the present invention, among cloned pAVQ CMV AS300KRib1-TK and pAVQ CMV AS100KRib2-TKs introducing TK gene (HSV-TK (herpes simplex virus thymidine kinase)) into the 3'exon of ribozyme, AS100KRib2- With TK, cell viability was observed through TK analysis. As a result of TK analysis, in HT-29 cells, there was no change in the luminescence of GFP when GCV was treated or untreated, indicating that there was no effect on the viability of the cells.

However, in SW480 cells, when the cells transfected with AS100KRib2-TK were treated with GCV, it could be seen that the number of GFP emission decreased compared to cells not treated with GCV.

On the other hand, an important point in gene therapy is the method of delivering recombinant genes to cells.

As a general method, there is a method of directly administering recombinant DNA by a physicochemical method and a recombinant viral vector as a biological method. The direct administration of DNA has the advantage of low risk and economy because it is simple, but it has the disadvantage of low delivery rate of recombinant DNA.

Accordingly, the present invention includes an adenovirus delivery system having low risk and excellent DNA delivery rate as a cell delivery method of the ribozyme.

Adenovirus is a DNA virus with a diameter of about 70-80 nm and a dsDNA of ^{20-26×10 6 Daltons inside.} There are inverted terminal repeats (ITRs) at both ends of the genome, where virus replication begins. The adenovirus genome is divided into the early regions of E1-E4 and the late regions of L1-L5.

The advantages of adenovirus vectors are: First, they are known as viruses that are irrelevant to the occurrence of tumors in the human body, and are low-risk viruses due to the development of long-term virus vaccines. Second, high titer viruses can be produced. Third, it can infect cells that have undergone meiosis and almost all human cells. Fourth, DNA close to 10 kb can be inserted into the adenovirus vector.

Disadvantages: First, adenoviruses do not have a permanent effect because they do not integrate into the host's genome. Second, the therapeutic effect is short due to the antigen-antibody reaction to the virus. Third, side effects cannot but be taken into account when administering a large number of drops.

According to Example 6 of the present invention, homologous recombination was performed by co-transformation of a ribozyme transfer vector and a pAdenovactor ΔE1/E3 backbone vector in a bacterium named BJ5183 to create a recombinant ribozyme, which was transfected into 293 cells. Recombinant ribozyme virus was obtained.

The resulting recombinant ribozyme virus infects and amplifies 293 cells. In order to confirm whether the recombinant ribozyme virus is properly made during the amplification process, viral genomic DNA is extracted and the TK gene of ribozyme and the LITR of the virus are identified through PCR. I did.

In addition, SW480 cells were infected and the TK gene was also confirmed at the RNA level through RT-PCR. This recombinant virus ribozyme sure they were purified using the ^Vivapure? AdenoPACK ^TM 100 RT.

The purified Ad-AS300KRib1-TK and Ad-AS100KRib2-TK viruses infected tumor cells and showed the specificity and efficacy of Ad-ribozyme in tumor cells. As a result of infection with SW480 cells, a trans-splicing band was seen in Ad-AS300KRib1-TK and Ad-AS100KRib2-TK, and it was confirmed that this occurred at the target site through sequencing.

According to Example 7 of the present invention, MTS analysis was performed to see that Ad-ribozymes specifically induce trans-splicing to induce transgenes. As a result, it was found that only Ad-ribozymes induced apoptosis in the Kras G12V mutated cell lines SW480 cells and CAPAN-1 cells when compared to the control. It was observed that it did not happen. This indicates that Ad-ribozyme can specifically recognize Kras G12V, trans-splicing, and induce a transgene to specifically induce cell death.

According to the eighth embodiment of the present invention, in the Ad- ribozyme In order to examine specificity and efficiency in vivo, a xenograft mice model experiment was performed.

As a result, in the Kras mutant tumor, the tumor weight of Ad-AS100KRib2-TK decreased compared to the control group. However, in the case of the Kras wild-type tumor, when compared with the negative control Ad-CMV-LacZ and the positive control Ad-CMV-TK, it was confirmed that Ad-ribozymes did not work in the Kras wild-type tumor.

These results show that Ad-ribozyme according to the present invention can specifically regress tumors expressing only Kras G12V.

As described above, the ribozyme of the present invention induces gene expression by correcting a cancer-specific gene with a therapeutic gene. As a result, only cancer cells can selectively induce cell death.

Therefore, the present invention provides an anticancer pharmaceutical composition comprising the ribozyme as an active ingredient.

The anticancer pharmaceutical composition of the present invention can be preferably formulated as a pharmaceutical composition, including at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration.

Pharmaceutically acceptable carriers included in the composition of the present invention are commonly used at the time of formulation, and acceptable pharmaceutical carriers in compositions formulated as liquid solutions are sterilized and suitable for living organisms, saline solution, sterile water , Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used, and other conventional additives such as antioxidants, buffers, bacteriostatic agents, etc. Can be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to form injection formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, or tablets. Thus, a target organ-specific antibody or other ligand may be used in combination with the carrier.

The pharmaceutical composition of the present invention is preferably parenterally administered, and may be administered using, for example, intravenous administration, intraperitoneal administration, intratumoral administration, intramuscular administration, subcutaneous administration, or local administration, but is not limited thereto. .

The dosage of the anticancer pharmaceutical composition of the present invention is the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of formulation and the age, weight, general health condition, sex and diet of the patient. , Administration time, administration route and secretion rate of the composition, treatment period, it may be adjusted according to various factors including drugs used simultaneously.

The pharmaceutical composition of the present invention may be used alone or in combination with auxiliary treatment methods such as surgical operation therapy. Chemotherapeutic agents that can be used with the composition of the present invention include cisplatin, carboplatin carboplatin, procarbazine, mechlorethamine, cyclophosphamide. ), ifosfamide, melphalan, chlorambucil, bisulfan, nitrosourea, dactinomycin, daunorubicin, doxorubicin (doxorubicin), bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, taxol, transplatinum, 5-fluorouracil, vincristin, vinblastin, and methotrexate. Radiotherapy that can be used with the composition of the invention is X-ray irradiation and -ray irradiation, and the like.

In addition, the ribozyme of the present invention can selectively diagnose only cancer cells by conjugating a reporter gene to a cancer-specific gene.

Accordingly, the present invention provides a composition for diagnosis of cancer comprising the ribozyme as an active ingredient.

[Example]

Hereinafter, the present invention will be described in more detail through examples. But. These examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1: Kras G12V Trans-splicing capable of specifically recognizing RNA Group I ribozyme production

1.K- ras Targeting Ribozyme design

The internal guide sequence (IGS) of ribozyme recognizes the target template RNA and triggers the trans-splicing mechanism, and the secondary structure of the target RNA has an effect.Therefore, the mfold program (RNA secondary structure form program) ) Was used to predict the secondary structure, and it was confirmed that ribozyme is an easy structure to cause trans-splicing in the 12th codon site to be targeted.

The secondary structure of Kras cDNA in which the 12th codon of Kras is replaced from Gly to Val was mutated by analyzing the secondary structure of Kras cDNA using the mfold program (program-copyright 1996 Dr. M. Zuker that analyzes the RNA secondary structure provided on the Web). It was confirmed that the 12th codon of Kras was a structure suitable for targeting ribozyme (see FIG. 2).

Compared with the result of finding and analyzing the part suitable for targeting ribozyme through the existing mapping method, it was confirmed that the secondary structure in the case of a single base mutation in the 12th codon of Kras from Gly to Val is a targetable structure. It was decided to create a specific ribozyme.

An internal guide sequence (IGS) of ribozyme was designed to target the mutation in which Kras' 12th codon was substituted from GGT to GTT. At this time, two ribozymes were designed: KRib1 (GCAGCT), in which IGS forms a G?U base pair with a mutated single base, and KRib2 (GACAGC), which forms a G?U base pair with the next base mutated (see FIG. 3). ).

2. K- ras 12V (substrate) structure fabrication

2-1. In vitro Mutation formation and Cloning

4 shows in vitro It shows the structure of Kras 12V produced from the Kras wild type through mutation formation.

GeneEditor in to create the target structure Using an in vitro site-directed mutagenesis system (Promega), Kras 12V was constructed in which the 12th codon from the Kras wild type was replaced with valine.

A primer of SEQ ID NO: 1 (see Table 1) was used, which was cloned into pUC19 as 5'BamHI, 3'HindIII.

Sequence number primer order One 5'-GTTGGAGCTGGTGGCGTAGGC-3 Kras wild 2 5'-TAATACGACTCACTA-3' Kras 5'BamHI 3 5'-GGGTAATACGACTCACTATAGGAGGTAAAAGTTATCAGGCATGC-3' kras rib T7-5' 4 5'-GGGTAATACGACTCACTATAGACAGCAAAAGTTATCAGGCATGC-3' RY-PCR 5 5'-TGTAAAACGACGGCCAGTG-3 RY-RT 6 5'-CGATGATCACGAAGACGCCAAAAACATA-3' kras p1p10-rib1-5 7 5'-CGACATGATCACGAAGACGCCAAAAACATA-3' kras p1p10-rib2-5 8 5'-AAGGAAAAAAGCGGCCGCTTATTACAATTTGGACTTT-3' krib 3' 9 5'-GGGAAGCTTGCAAGAGTGCCTTGACGA-3 kras as 5' 10 5'-GGGAAGGCTTCCATCAATTACTACTTGC-3 kras as 3' 11 5'-GGGTAATACGACTCACTATAGGGCTACTAGGACCATAGGTA-3' kras as300 5' 12 5'-CGCGGATCCACTGAATATAAACTTGTGGTA-3' kras t/s BamHI5' 13 5'-CCCAAGCTTGCCCAACACCGGCATAAAG-3 cell t/s luci 3'nest 14 5'-GTGATCATCGCGATGATCACGCTTCGTACCCCTGCCAT-3' TK 5'NruI 1set 15 5'-GTGATCATCGCGACATGATCACGCTTCGTACCCCTGCCAT-3' TK 5'NruI 2setI 16 5'-AAGGAAAAAATTCGAATTAGCCTCCCCCAT-3' 3'TK BstBI 17 5'-TAATACGACTCACTATAGGG-3' T7-R-Primer 18 5'-CCTTTCCCGCAATTTGACGGTCTT-3' IGS rev seq 19 5'-CGGGAATTCGTGGTAATGACAAGC-3' 5'TK stable 20 5'-CGGGGATCCATCCAGGATAAAGACGTGCATGGG-3' 3'TK stable 21 5'-GGAATTCTGGAGTTTGTGACGTGGCG-3' 5'LITR EcoRI 22 5'-GCTCTAGATGGCCAAATCTTACTCGGTTACGC-3' 3'LITR XbaI 23 5'-GGAATTCATGGTCGTTTTACAACGTCGTG-3' 5'viral LacZ 24 5'-GGGAAGCTTCGGATTGACCGTAATGGGA-3' cancer.lacZ-3

2-1-1. Preparation of vectors and inserts

1 μg of Kras PCR product DNA was reacted with BamHI (0.3u)/ HindⅢ (0.3u) and 10X B buffer (Roche) up to 20 μl of dH ₂ O at 37° C. for 3 hours and subjected to electrophoresis on a 2.5% TBE gel. Was confirmed. Then, 3 μg of pUC19 vector was also treated with BamHI (0.3u)/HindIII (0.3u) in the same manner to confirm that it was cut, and then subjected to phenol & EtOH precipitation reaction and quantified.

2-1-2. DNA Elution( insert )

Using gel extraction (DNA) (Omega bio tec.EZNA Kit), a 0.5 X TAE agarose gel was made at a concentration suitable for the size of DNA, loaded with DNA, and then checked the band with long wave UV, and only the desired band was cut out exactly. .

Each gel piece was put in a 1.5 µl tube so as to be 50-300 mg, and 0.5 µl of elution buffer was added thereto and completely dissolved at 60°C for 10 minutes. After completely dissolving the gel, insert the gel extraction column into the sample tube, transfer the dissolved solution to the column, turn it at 13000 rpm for 60 seconds, discard the settled solution, add 0.5 µl of Wash I buffer to each column, turn it for 60 seconds, and then remove the filtered buffer again. I discarded it.

After transferring the column to a new 1.5 µl tube, _{30 µl of dH 2} O was added, stored for 1 minute, centrifuged for 2 minutes to obtain DNA, quantified, and stored at -20°C.

2-1-3. connect

The enzyme-treated pUC19 and the trans-splicing product were reacted at 4° C. for 16 hours with T₄ligase (Roche) in a vector:insert (1:3) ratio, respectively.

2-1-4. Transformation

To transform the ligated product into E. coli (JM109), 1 µl of the ligated product was added to JM109 made of a soluble cell, and the electrophorator was set to 25 µF, 1.8 Kv, and a pulse controller of 400 Ω. After transforming by setting, it was put in 1ml fresh medium, mixed well, and incubated for 1 hour.

After spreading evenly on an agar plate made with X-gal and IPTG, incubated for 16 hours in an incubator at 37°C, selectively inoculate white colonies in LB medium containing 5ml ampicillin through color screening and shaken at 37°C for 16 hours. Cultured.

2-2. Base sequence confirmation

In The nucleotide sequence of Kras 12V produced through in vitro mutation formation was confirmed. Terminator ready reaction mixture (PE applied Biosystems) 3µl, quantified DNA 100ng, primer of SEQ ID NO: 2 (see Table 1) 3.2pmol in a total of 10µl reaction (96℃-10', 50℃ -5', 60°C -4') × 25 cycles were reacted.

Afterwards, _{40 µl of dH 2} O was added for purification, and then 3M NaoAC (1/10 volume) and 100% EtOH (2 volume) were added. After vortex, centrifuged at 13000 rpm at 4° C. for 30 minutes and 70% EtOH (400 µl) ), EtOH was removed, dried with speed-vacuum, and dissolved in 15 µl of a template suppression reagent. Subsequently, after vortex & spin down, it was transferred to a sequencing tube and sequencing was performed with an automatic sequencer (ABI 310 Genetic Analyzer).

3. Temperament RNA (K- ras ) Of the manufacture

3-1. K- ras Substrate manufacturing

Kras 12V to be used as a substrate and Kras wild-type DNA to be used as a control were cut with Hind III, extracted with phenol, and precipitated with EtoH.

3-2. Temperament warrior

RNA is made through transcription of the DNA prepared in the same manner as in 2-1 above. DNA template (1㎍), 1x transcription buffer, 10mM DTT (Sigma), 0.5mM ATP, GTP, CTP, UTP (Roche), 80U RNase inhibitor (Kosco), T7 RNA polymerase (Takara), and DEPC-H ₂ O were added to 100 µl, mixed, and reacted at 37°C for 3 hours.

To this end, a T7 promoter part is attached when making the 5'primer. After that, in order to remove the remaining DNA, 5U DNase I (promega) is treated at 37°C for 30 minutes to completely remove the DNA template and then phenol extraction (PH7.0) , After pure RNA was separated and purified through ethanol precipitation, it was concentrated in TE buffer (10mM Tris-Hcl PH7.5, 1mM EDTA).

4. KRib1 , KRib2 ( Kras targeting ribozyme ) Produce

4-1. Ribozyme Substrate manufacturing

Using the primers of SEQ ID NOs 3 and 4 (see Table 1) to construct a ribozyme having an internal guide sequence (IGS) capable of trans-splicing by recognizing the 12th codon of Kras. KRib1 and KRib2 were prepared by PCR from pt7L21. In addition, d)KRib1, d)KRib2, from which the catalytic core was removed from d)pt7L21 through PCR, was prepared and used as a control.

4-2. Ribozyme Warrior

Transfer is carried out in the same way as the substrate, in which case self-splicing is prevented as much as possible by increasing the amount of dNTP to 1.5mM, and 1x splicing buffer (40Mm Tris (ph7.5), 5mM MgCl ₂ , 10mM DTT, 4mM spermidin) ) Was used.

5. RNA Elution

In order to obtain only the desired RNA, 1/2 volume of the RNA solution was mixed with a denatured RNA loading dye (10 μl Formamide, 10 mM EDTA, 0.01% Bromophenol blue, 0.01% Xylenecyanol), and then treated at 95° C. for 5 minutes to denature.

After loading the denatured RNA on a 6% polyacrylamide gel containing urea, electrophoresis in 0.5x TBE buffer for 40 minutes at 230V, cut the gel of the RNA band of the desired size and elution buffer (0.6M Ammonium acetate, 1mM EDTA). , 0.2% SDS) was added to 400µl and reacted at 37°C for 3 hours. Then, the gel was settled by spin down, the supernatant was picked, purified through phenol extraction and EtOH precipitation, and finally concentrated in TE buffer, and RNA was quantified using a UV-spectrophotometer. At this time, ribozyme was quantified by eluting only the non-self-splicing product and eluting with a UV-spectrophotometer.

6. Phenol extraction and ethanol precipitation

Phenol: chloroform: isoamyl alcohol (25:24:1) in the same amount as the solution was added, thoroughly mixed with vortex, and centrifuged at 4°C for 10 minutes at 10000×g. Only the supernatant was carefully transferred to a 1.5ml tube, and then 2 times the volume of 100% EtOH (-70°C) and 1/10 volume of 3M sodium acetate were added and mixed well, and then added at -70°C for 40 minutes.

After centrifugation at 4℃ for 30 minutes, carefully remove the supernatant, wash the wall evenly with 400µl of 70% EtOH (-70℃), centrifuge for 10 minutes, remove all EtOH, dry for 10 seconds, and TE buffer Melted in.

Example 2: In In vitro Trans- splicing Ribozyme Confirmation of specificity of KRib1 and KRib2

1.Trans- Splicing reaction

In order to confirm the specificity of the ribozymes KRib1 and KRib2 designed in Example 1, a trans-splicing reaction was first performed in a test tube. In Kras G12V RNA (10nM) prepared through in vitro mutation formation and RNA of KRib1 and KRib2 ribozyme (50nM) were trans-spliced in vitro.

For the trans-splicing reaction of ribozyme (KRib1, KRib2) with specific IGS and Kras, the absolute amount of substrate RNA and ribozyme was set to 10nM: 50nM, and substrate RNA (2x reaction buffer, substrate RNA, 0.2mM dGTP, DEPC-H ₂ O) was preheated at 37° C. for 5 minutes in advance. Ribozyme RNA (2x reaction buffer, Ribozyme RNA, DEPC-H ₂ O) was reacted at 50°C for 5 minutes and then reacted at 37°C for 2 minutes to induce the formation of the correct tertiary structure, and then mix the two reactants well. It was reacted at ℃ for 3 hours.

2. Reverse transcription

A well-mixed 3'primer of SEQ ID NO: 5 (see Table 1), 5x RT buffer, and a trans-splicing product (10 µl) that bind to the 3'exon (Ribozyme) part of the trans-spliced RNA transcript. Then, it was reacted at 65° C. for 5 minutes and then stored at room temperature for 10 minutes.

After storage at room temperature, a total of 50µl was made with 0.5mM dNTP (BMS), MMLV reverse transcriptase 1U (Promega), and DEPC dH ₂ 0 and reacted at 37°C for 1 hour. After reacting at 95° C. for 5 minutes, the activity of MMLV-RT was completely removed and then stored at 4° C.

3. PCR

_{The reaction product (20 µl) after the RT reaction was added with 50 mM MgCl 2} and 5% DMSO (63° C. 20 sec annealing/ 25 cycles) using the primers of SEQ ID NOs: 2 and 5 (see Table 1), and PCR was performed.

4. Cloning ( RT - PCR Product) and sequencing

RT-PCR product cloning (same as 2-1 of Example 1) was performed on pUC19, and sequencing (with 2-2 of Example 2 above) using a primer of SEQ ID NO: 2 (see Table 1) (3.2 pmol) Same) was carried out.

5 shows in It shows the analysis of Kras G12V trans-splicing products of KRib1 and KRib2 in vitro [A: RT-PCR analysis, BC: sequencing (B: KRib1, C: KRib2)].

Referring to FIG. 5A, RT-PCR was performed using a 5'primer that binds to Kras and a 3'primer that binds to a ribozyme 3'exon. We got a product-sized band that could come out when splicing took place.

On the other hand, when the inactive ribozymes (d)KRib1, d)KRib2) and Kras G12V RNA were reacted with the catalytic core site removed, or when only KRib1 and KRib2 and wild-type Kras RNA were reacted, any product was not seen. Couldn't.

In addition, referring to Figs. 5B and 5C, as a result of sequencing after cloning the PCR product, trans-splicing occurs accurately at the target site, so that the nucleotide sequence of Kras is present in 5'and the 3'exon of ribozyme is in the 3'side. It was confirmed that the nucleotide sequence was present.

These results Through a ribozyme that targets the KRib1 and KRib2 Kras G12V in In vitro, it was confirmed that Kras G12V was specifically recognized and cleaved, and the 3'exon of ribozyme was linked to the correct target site.

Example 3: Trans-splicing according to the degree of deformation Ribozyme in Confirmation of efficacy and specificity in vitro

By modifying the P1/P10 helix and the antisense site in addition to IGS, which is a target-specific six nucleotide sequence, the specificity and efficiency of the trans-splicing ribozyme can be increased.In designing such an enhanced ribozyme Each part was gradually tried to confirm the specificity and efficiency according to the degree of deformation.

6 shows a trans-splicing ribozyme with increased specificity and efficiency by modifying the P1/P10 helix and the antisense site.

Referring to Figure 6, ribozyme with only IGS, ribozyme with P1/P10 structure added, ribozyme with 100 or 300 antisense, and thus modified ribozyme RNA series to which each site is gradually added are two types of KRib1 and KRib2. Each was prepared for ribozyme.

1. Specificity increased specificity Ribozyme making

In the IGS of ribozyme, the 3'exon site was subjected to PCR using a primer of SEQ ID NO: 6, a primer of SEQ ID NO: 8 / a primer of SEQ ID NO: 7 and a primer of SEQ ID NO: 8 (see Table 1), followed by Hind III and Nru I. It was cloned into the SEAP promoter vector.

After the ribozyme cloned into the vector, luciferase was cloned with Nru I and Xba I.At this time, luciferase, a 3'exon, was linked to Kras and an extra nucleotide was added in front of the luciferase gene so that the protein of the transgene was correctly expressed. I guessed it.

After that, the complementary 100 nt, 300 nt antisense strand toward the 3'end from the place recognized by IGS on the Kras sequence was used as a primer of SEQ ID NO: 9 and a primer of SEQ ID NO: 10 / a primer of SEQ ID NO: 9 and a primer of SEQ ID NO: 11 (Table 1) was used to perform PCR, which was cloned into a Hind III enzyme site in front of the IGS of the SEAP KRib 1 and SEAP KRib 2 constructs.

The CMV promoter was cloned from the completed SEAP-KRib 1, SEAP KRib 2, SEAP AS100 KRib1, SEAP AS100 KRib2, SEAP AS300 KRib1, and SEAP AS300 KRib2 as pAV 3.0 vectors using BamH I and Not I sites, respectively. A set of ribozyme structures with excitation was produced.

2. Trans- Splicing Ribozyme in vitro Efficiency and specificity

Each of the ribozymes (50nM) produced above in vitro RT-PCR as in Example 2 using a 5'primer binding to Kras and a 3'primer binding to a ribozyme 3'exon after trans-splicing reaction with Kras wild-type RNA or Kras G12V RNA (10 nM). Was performed.

7 is in The results of trans-splicing efficiency and specificity analysis of the modified ribozyme in vitro are shown.

Referring to Figures 7A and 7B, in a sample obtained by reacting KRib1 or KRib2 with Kras G12V RNA, a band having a product size that can be produced when trans-splicing occurs was obtained.

in vitro As a result of the trans-splicing reaction experiment of 2 sets of KRib1 according to the degree of transformation in the phase, the amount of trans-conjugation (t/s) product of ribozyme having 300 pieces of ribozyme having 300 pieces was higher than that of ribozyme having 100 pieces of antisense. Many were confirmed by PCR, and in the case of KRib2, it was confirmed by PCR that the amount of the trans-conjugation product of the ribozyme having 100 antisense and the ribozyme having 300 is the same.

In addition, the PCR band of the same size as the trans-splicing product was blurred even in the sample trans-spliced with Kras wild-type RNA according to the degree of modification, but as a result of sequencing after cloning, the trans-spliced ribo It could be confirmed that the zyme was PCR or that the substrate was a PCR product of non-specific PCR.

In addition, when the inactive ribozyme (d)KRib1, d)KRib2) and Kras RNA were reacted with the catalytic core portion removed, or when only ribozyme and nocturnal Kras RNA were reacted, no product was seen.

7C and 7D, as a result of sequencing after cloning the PCR product, trans-splicing occurs accurately at the target site, so that the nucleotide sequence of Kras is present in 5'and the 3'exon of ribozyme is in the 3'side. It was confirmed that the luciferase (Luciferase) nucleotide sequence was present.

Example 4: Trans- in cell line Splicing Specificity, efficiency check

In order to investigate whether specific ribozyme trans-splicing a specific gene attached to ribozyme as a target of Kras G12V RNA, which is a single base mutated intracellularly, firefly lucifer on 3'exon in 293 cells expressing Kras wild type. A ribozyme tagged with Rase was designed and a reporter essay was performed.

The luciferase-tagged ribozyme targets Kras G12V RNA in which the 12th codon has a single base mutation from Gly (ggt) to Val (gtt).At this time, KRib1( Two ribozymes were designed: one set of GCAGCT) and two sets of KRib2 (GACAGC) that formed a G?U base pair with the next base mutated.

The 1 set and 2 sets of ribozymes designed in this way produced 1 set of AS100KRib/ AS300KRib, 2 sets of structures, pAV AS100 KRib1, and pAV as300 KRib1 structures in the pAV3.0 vector. Trans-conjugation product analysis was performed in 293 cells expressing Kras wild type using cloned ribozymes. The substrate Kras G12V was co-transfected with RNA and ribozyme with DNA plasmid.

1. Cell culture

293 cells were cultured in a medium supplemented with 10% FBS (fetal bovine serum), DMEM (Dulbecco's modified eagle medium; HyClone), and 0.5% antibiotic/antimycotic solution at 37°C in a 5% CO₂ incubator, and passaged every 3 to 4 days. Cultured.

At this time, after washing the cells with 1X PBS (8g NaCl, 0.2g KCl, 1.14g Na ₂ HPO ₄ , 0.2g KH ₄ PO ₄ /L), 1x trypsin/EDTA (8.2g NaCl, 0.2g KCl, 1.14g Na ₂ HPO₄, 0.2g KH ₂ PO ₄ , _{0.029g Na 2} EDTA?dH ₂ 0, 1g trypsin, pH 7.35/L) Treat 1 ml of CO ₂ Placed in the incubator for 1 to 3 minutes. After inactivating trypsin with 9 ml of medium, centrifugation was performed at 1500×g for 2 minutes and 30 seconds to remove the supernatant and resuspended in medium. 1/3 of these were seeded in a new 100mm dish and cultured.

2. DMRIE By -C DNA , RNA Court Transfection

The DNA and Kras RNA of the constructs of FIGS. 8A and 9A obtained by cloning (prepared in the same manner as in Example 1 3-2) were coat-transfected into 293 cells. Reduced serum media (Reduced serum media) 1 µg of construct DNA was added to 300 µl of Opti-MEMI, and then mixed with a tube containing 3 µl of DMRIE-C (Invitrogen) in 300 µl of Opti-MEMI, and reacted at room temperature for 30 minutes.

Kras wild type and Kras 12V RNA 4㎍ were added to 600 µl of Opti-MEMI and 3 µl of DMRIE-C, mixed, and then overlaid on the washed cells. _{After incubation in a 5% CO 2} incubator for 4 hours, complete growth media was replaced.

3. Dual Luciferase analysis

Remove the medium of each cell transfected into a 35mm dish and clean well with 1x PBS. Here, 200 µl of 1x passive lysis buffer was added and lysed at room temperature for 15 minutes, and the cells were harvested and centrifuged at 13000 rpm for 30 seconds to transfer only the supernatant to a new tube.

100 µl of LARII (Luciferase Assay Reagent II) was added to a luminometer tube, 20 µl of cell lysate was added thereto, mixed, and read with a luminometer. Again, 100 µl of Stop & Glo reagent mix (Stop & Glo 20 µl + Stop & Glo buffer 1 ㎖) was added thereto, mixed, and read with a luminometer (TD+20/20). The delay time was set to 3 seconds, the integral time was set to 12 seconds, and the sensitivity level was set to 60% appropriate for each cell.

4. RT - PCR through Intracellular Trans- Splicing Confirmation of product expression

4-1. RNA Separation

To isolate total RNA from cells, Trizol (Invitrogen) to which 20mM EDTA was added was used. Based on the manual, 1 ml of Trizol was treated, incubated for 5 minutes, cells were removed, 200 μl of chloroform was added, vortexed, and centrifuged in a centrifuge at 4° C. for 10 minutes. After transferring the supernatant to a new tube, EtOH was precipitated. Then DNase (Promega) was treated.

4-2. Reverse transcription

Of the total RNA isolated in 2 above, 5 µl of the total RNA was mixed well using OligodT (Invitrigen) to which L-arginine amide was added, and then incubated at 65° C. for 5 minutes, and then stored at 4° C. for 5 minutes. Then, 5x RT buffer, 0.5mM dNTP (BMS), MMLV reverse transcriptase 1U (Promega), and DEPC dH ₂ 0 were used to make a total of 25 µl and reacted at 37°C for 1 hour. Thereafter, it was reacted at 95° C. for 5 minutes to completely remove the activity of MMLV-RT and then stored at 4° C.

4-3. PCR

The cDNA after the RT reaction was PCR buffer, dNTP, PCR tag polymerase, and 5% DMSO (58° C. 30 sec annealing/ 30 cycles) using primers of SEQ ID NOs: 12 and 13 (see Table 1). GAPDH used as a loading control was PCR buffered, dNTP, and PCR tag polymerase using primers.

4-4. Cloning ( RT - PCR Product) and sequencing

The RT-PCR product was cloned into the TA-vector using the pGEM-T easy vector system (Promega), and sequencing was performed using 3.2 pmol of the primer of SEQ ID NO: 17 (see Table 1).

4-4-1. RT - PCR Product elution

DNA was eluted in the same manner as in Example 1 2-1-2 using DNA gel extraction (Bio basic inc.).

4-4-2. connect

The TA-vector and the trans-splicing product (DNA) eluted with the RT-PCR product were ligated in the same manner as in 2-1-3 of Example 1.

4-4-3. Transformation

The ligation product was transformed into E. coli (JM109) in the same manner as in 2-1-4 of Example 1.

4-4-4. Sequence analysis through sequencing

The colony was inoculated and the DNA obtained by mini-preparation was cut with EcoRI to obtain a clone containing the insert. Sequences were confirmed through sequencing in the same manner as in Example 1 2-2.

5. Trans- Splicing Specificity, efficiency check

Figure 8B shows the results of reporter assay of transgene by trans-splicing ribozyme.

Referring to FIG. 8B, when pAV AS100 KRib1 was co-transfected with Kras wild type or Kras G12V, there was no expression of luciferase in the sample to which Kras wild type was added, whereas in the sample to which Kras G12V was added, luciferase was expressed in a small amount. I was able to confirm that it was done.

However, pAV AS300 KRib1 was able to observe higher luciferase values in the Kras G12V sample than in the Kras wild-type sample, but it was observed that the transgene was not specifically expressed in Kras G12V. Luciferase was not expressed in the sample to which only the mock or substrate (Kras G12V) used as the control was added, and the sample of the vector control group.

From these results, it could be observed that AS100KRib1 specifically expresses the transgene in Kras G12V in cells as well as the results confirmed in vitro.

9B shows the results of RT-PCR analysis to confirm the selective expression of transgenes by trans-splicing ribozyme.

Referring to FIG. 9B, in the Krib 1 set, only KRAS G12V RNA and AS300KRib1-F, luc (lane 8) could specifically see the band of the T/S product. In addition, in the 2 sets, only KRAS G12V RNA and AS100KRib2-F.luc (lane 6) could specifically see the T/S product band.

To determine whether this specific band is a trans-conjugation product and whether splicing occurred at the correct site, the trans-splicing band was sequenced and confirmed. As a result, it was found that trans-splicing occurred at the correct site. From this, it was confirmed that the ribozyme of the present invention causes trans-splicing by specifically distinguishing a single base mutation of Kras wild type and Kras G12V.

Example 5: In In vivo trans-splicing confirmed apoptosis induced by transgene expression

Group I ribozymes can induce the expression of new trasgenes by not only recognizing and cutting specific sites, but also by connecting their 3'exons to the 5'exons of the target site. Therefore, by inserting the HSV-TK (thymidine kinase) gene into the 3'exon of Kras ribozyme, treatment with GCV, a prodrug, specifically induces cell death in cells expressing a new trans-spliced transgene. do.

Figure 10A shows the structure for TK analysis in SW480 cells.

Referring to FIG. 10A, in order to determine whether a ribozyme into which a TK gene is introduced can induce cell death, a structure in which a TK gene is inserted into a pAVQ transfer vector was first constructed.

One. Kras - Ribozyme - TK Structure Cloning

1-1. Prepare vectors and inserts

With AS300KRib1-F.luc and AS100KRib2-F.luc, cloned to insert the TK gene of HSV-TK instead of F. luciferase in the 3'exon.

3 μg of the ribozyme constructs, which were pAVQ vectors, were cut at 37° C. for 3 hours using BglII (3U, Rocho) and BstBI (3U, NEB) restriction enzymes, and after confirming that they were cut off by hanging on a 1% TAE gel, the plasmid was eluted.

To obtain the TK gene, PCR [96°C-5′> with the primers of SEQ ID NOs: 14 and 15 and primers of SEQ ID NO: 16 (see Table 1) using the construct of pCDNA3.1(+) CMV-TK → (96℃-30", 58℃-1'30", 72℃-1'30") × 30 cycles → 72℃-7'].

_{After phenol extraction and ethanol precipitation of the prepared TK DNA, dH 2} O was added to 3 μg using NruI (3U; Rocho) and BstBI (3U; NEB) restriction enzymes to the final 50 µl, mixed, and reacted at 37° C. for 3 hours. DNA was purified through phenol extraction and ethanol precipitation and dissolved in _{dH 2 O.}

1-2. connect

The enzyme-treated pAVQ KRib1/KRib2 vector and the insert (TK gene) were reacted at 4° C. for 16 hours with T₄ligase (Roche) in a vector:insert (1:3) ratio.

1-3. Transformation

The ligated vector and the insert were transformed into DH5α-soluble cells by heat shock for 1 minute and 30 seconds at 42° C., stored on ice for 5 minutes, and incubated at 37° C. for 30 minutes by adding 1 ml of new LB. Thereafter, the kanamycin agar plate was evenly spread and incubated for 16 hours in an incubator at 37°C. The colonies were inoculated in 5 ml LB medium containing ampicillin and incubated with shaking at 37°C for 16 hours.

1-4. Through sequencing Cloning Confirm

The DNA obtained by mini-preparation by inoculating colonies was confirmed by sequencing the primer of SEQ ID NO: 18 (see Table 1) in the same manner as in Example 1 2-2.

2. Analysis of suicide gene activity

One day before the experiment, SW480 (Kras G12V) cells and HT-29 (wild type Kras) cells were cultured in a 35 mm dish with 2×10 ⁵ cells. The cloned construct of Fig. 10A was co-transfected with pEGFP-NI (250 ng).

2-1. DNA Transfection

Together with the construct, pEGFP-NI (250 ng) was co-transfected using welfec M Gold transfection reagent (Welgen). After washing the cells with PBS, 2 ml of the reduced serum medium OPTI-MEM was added and cultured in _{a 37° C. 5% CO 2 incubator.} After mixing 250 ng of GFP and 1 µg of ribozyme in 100 µl of the reduced serum medium OPTI-MEM, 4 µl of gold enhancer was diluted in 100 ul of OPTI-MEM, mixed with DNA mixture, and incubated for 15 minutes.

After reacting the DNA mixture with 6 µl of M gold diluted in 100 µl of OPTI-MEM, the mixture was incubated for 15 minutes. After cultivation, it was added evenly on the cells. Then, after incubation for 5 hours in a 37°C 5% CO ₂ incubator, it was replaced with Complete Media.

2-2. Observation of cell viability

After 24 hours, ^{200 μM GCV (Cymevene?, Roche} ) was added to give each dish and cultured for 3 days. AxioCam HR4 version 5.05.10. Using a Zeiss microscope, the number of GFP emission was measured in the transfected cells with a luminous wavelength of 9 filters (488 to 509 nm). Cell viability (%) was calculated using the following formula.

[Equation 1]

3. Confirmation of induction of cell death

AS100KRib2-TK was transfected with the GFP gene into the cell line HT-29 endogenously expressing Kras wild type and the cell line SW480 endogenously expressing Kras G12V in a plasmid state.

Referring to FIG. 10B, in HT-29 cells, when GCV was treated or untreated, there was no change in the luminescence of GFP, so it could be seen that there was no effect on the viability of the cells.

However, in SW480 cells, when the cells transfected with AS100KRib2-TK were treated with GCV, it could be seen that the number of GFP emission decreased compared to cells not treated with GCV. It can be seen that AS100KRib2-TK reduced cell viability by changing the prodrug GCV to toxin by expression of the TK gene by specific trans-splicing.

From these results, it was confirmed that the ribozyme of the present invention specifically distinguishes between wild-type Kras and mutated Kras and trans-splicing.

Example 6: Adenovirus Fabrication of virus structure for delivery system

Homologous recombination of the transfer vector ribozyme and the pAdenovactor ΔE1/E3 backbone vector by co-transfecting the bacteria of the BJ5183 strain with the pAdenovactor ΔE1/E3 backbone vector together with the pAVQ transfer vector ribozyme, a structure in which the TK gene is inserted into the pAVQ transfer vector. Made it. In this way, the adenovirus recombinant trans-splicing ribozyme of FIG. 11B was constructed.

1. Recombination for development of delivery systems Adenovirus vector

The cloned pAdenovactor-CMV5-IRES-GFP transfer vector (Qbiogene) of FIG. 10A was homologously recombined by co-transformation with pAdenovactor ΔE1/E3 backbone vector (Qbiogene) in bacteria (BJ5183) (see FIG. 11A).

First, the transfer vector was linearized with restriction enzyme PmeI, purified through phenol extraction and ethanol precipitation, and quantified, and then 1 μg and 100 ng of pAdenovactor ΔE1/E3 backbone vector were co-transformed into BJ5183.

The recombinant vectors homologously recombined in BJ5183 of FIG. 11B thus obtained were linearized with PacI, purified through phenol extraction and ethanol precipitation, quantified, and transfected into 293 cells. Linearized recombinant vectors transfected into 293 cells produced recombinant adenovirus through 3 plaque purification.

Recombinant virus was amplified using 293 cells was purified using the ^{Vivapure? AdenoPACK TM 100 RT (Sartorius} AG.) And concentrated. To determine the dropwise addition of recombinant adenoviruses, a tissue culture infectious dose for 50% of the cells (TCID50) method was used. Viral stocks were stored at -80°C with 10% sucrose.

1-1. Before refining Ad - AS300KRib1 - TK Analysis of

Homologously recombined virus Recombinant ribozymes were transfected into 293 cells to obtain Ad-ribozyme-TK virus with infectious ability. Since these viruses have low drop rates, high drop rates must be obtained through multiple infections in 293 cells. When a high-cost virus is obtained, pure viruses are purified through a purification process.

Therefore, before purifying viruses, it is necessary to check whether the virus is well produced and that the correct Ad-ribozymes are being made. In addition, it is necessary to select a clone with good efficiency among several clones. To confirm this, the virus genome was obtained at a low drop rate among several infections, and PCR was performed for the TK (thymidine kinase) gene of the 3'exon of ribozyme and the left inverted terminal repeat (LITR) of the pAdenovactor ΔE1/E3 backbone vector through PCR. It was confirmed through (Fig. 12A).

In addition, low dropwise Ad-AS300KRib1-TK was infected with Kras G12V mutated cell line SW480 cells to confirm the expression of Ad-AS300KRib1-TK (FIG. 12B). Virus was purified by comparing the bands of the clones with clone 18.

1-2. Before refining Ad - AS100KRib2 - TK Analysis of

Ad-AS100KRib2-TK was analyzed in the same manner as in 1-1 (Fig. 13). As a result of pulling out the virus genome and performing PCR, it was confirmed that the TK (thymidine kinase) gene of the 3'exon of ribozyme and the left inverted terminal repeat (LITR) of the pAdenovactor ΔE1/E3 backbone vector (Fig. Then, SW480 cells were infected to confirm the expression of Ad-AS100KRib2-TK (Fig. 13B). Virus was purified with clone 1 as a result of comparing the bands of the clones.

1-3. Before refining Ad - AS100KRib2 - LacZ Analysis of

Ad-AS100KRib2-LacZ was analyzed in the same manner as in 1-1 (Fig. 14). As a result of PCR by extracting the virus genome, it was confirmed that the LacZ gene of the 3'exon of ribozyme and the left inverted terminal repeat (LITR) of the pAdenovactor ΔE1/E3 backbone vector (Fig. 14A). Then, SW480 cells were infected to confirm the expression of Ad-AS100KRib2-LacZ (FIG. 14B). Virus was purified with clone No. 30 as a result of comparing the bands of the clones.

2. Identification of recombinant virus

In the middle of making recombinant adenovirus through three plaque purification, virus genomic DNA was extracted to check whether the virus is being properly made in 293 cells infected with the virus, and PCR was performed with primers of SEQ ID NOs: 19 to 24 (see Table 1). Amplified through [96℃-5'→(96℃-30", 58℃-1'30", 72℃-1') × 30 cycles → 72℃-7'], and 2% TBE agarose gel The size was checked by loading. In addition, it was injected into SW480 cells, and recombinant viruses were confirmed through RT-PCR in the same manner as in Example 4 5 and 6 above.

3. Trans- of viral recombinations Splicing Confirm

After infecting the Ad-ribozymes purified in 1 above with a virus of 50 MOI in the Kras G12V mutated cell line SW480, 48 hours later, primers of SEQ ID NOs: 1 and 14 in the same manner as 11-3 and 4 (see Table 1). ) With RT-PCR and a primer of SEQ ID NO: 17 (see Table 1) through sequencing to confirm trans-splicing.

4. In tumor cells Ad - Ribozyme Confirmation of used T/S product

Ad-ribozyme thus prepared was infected with Ad-ribozyme in SW480 cells, a Kras G12V mutant cell line, in order to confirm whether a T/S product was produced by trans-splicing specifically in tumor cells. As a control, it was mixed with Ad-CMV-TK and used. Ad-CMV-TK is the same gene as the TK gene of the 3'exon of ribozyme, and is a structure without ribozyme. Mixing (Mix) is in when RNA extraction To show that trans-splicing does not occur in vitro, the endogenous mutant Kras of SW480 cells and the endogenous Kras wild-type HT-29 cells were reacted with Ad-AS100KRib2-TK in a tube.

15 shows the analysis results of trans-conjugated RNA products using an adenovirus delivery system in Kras G12V mutated SW480 cells.

Referring to FIG. 15, it can be seen that, while the control group did not have a band, a band was specifically visible only in the lanes infected with Ad-AS300KRib1-TK and Ad0AS100KRib2-TK.

It was confirmed through sequencing to confirm whether this specific band was a specific T/S product by ribozyme. As a result, it was found that Ad-ribozymes were specific and functioning correctly.

Example 7: Adenovirus Kras G12V - Kras by specificity ribozyme G12V Specific apoptosis in the cancer cells impassioned stones

MTS analysis was performed to test whether a specific ribozyme targeting Kras G12V induces cell death in Kras G12V mutated cancer cells. The cell deaths of cancer cells were observed by infecting the Kras G12V mutated cell lines SW480 cells, CAPAN-1 cells, and Kras wild-type HT-29 cells with Ad-ribozymes and treatment with GCV the next day.

1. Cell culture

HT-29 (colorectal adenocarcinoma) is a medium supplemented with 10% FBS (fetal bovine serum), DMEM (Dulbecco's modified eagle medium; HyClone), and 0.5% antibiotic/antimycotic solution. serum), RPMI 1640 (Roswell Park Memorial Institute 1640; HyClone), 0.5% antibiotic/antifungal solution is added. CAPAN-1 (pancreatic adenocarcinoma) is 10% FBS (fetal bovine serum), RPMI 1640 (Roswell Park Memorial Institute) 1640; HyClone), 0.5% antibiotic/antimycotic solution was added, and cultured in a 5% CO₂ incubator at 37°C, and subcultured every 3 to 4 days.

At this time, after washing the cells with 1X PBS (8g NaCl, 0.2g KCl, 1.14g Na ₂ HPO ₄ , 0.2g KH ₄ PO ₄ /L), 1x trypsin/EDTA (8.2g NaCl, 0.2g KCl, 1.14g Na ₂ HPO₄, 0.2g KH ₂ PO ₄ , _{0.029g Na 2} EDTA?dH ₂ 0, 1g trypsin, pH 7.35/L) Treat 1 ml of CO ₂ Placed in the incubator for 1 to 3 minutes. After inactivating trypsin with 9 ml of medium, centrifugation was performed at 1500×g for 2 minutes and 30 seconds to remove the supernatant and resuspended in medium. 1/3 of these were seeded in a new 100mm dish and cultured.

2. Cell proliferation assay

The cell proliferation (MTS) assay was performed based on the manual of CellTiter 96Aqueous one solution reagent (MTS, Promega).

Cells were seeded in a 96-well plate at 3×10 ³ cells/well (0.1 ml). After incubating overnight in a 37° C. 5% CO ₂ incubator, each well was infected with viruses of various MOIs. After 16 hours to process each plate ^{100 uM GCV (Cymevene?, Roche} ) were incubated for 5 days. Add 20% of CellTiter 96Aqueous one solution reagent (MTS, Promega) to 100ul of Opti-MEM, add it to each well, and incubate in a 37℃ 5% CO ₂ incubator for 1-4 hours, and then increase the cell viability at 490nm. It was measured.

3 . Kras G12V Confirmation of specific apoptosis in mutated cancer cells

16A shows the results of MTS analysis in SW480 cells.

Referring to the left graph of FIG. 16A, when GCV was treated with 100 μM in the same manner, Ad-ribozymes were M.O.I-dependently infected. Referring to the graph on the right of FIG. 16A, Ad-ribozymes were infected with 150 M.O.I and treated for each GCV dose.

Ad-CMV-TK and Ad-CMV-ribozyme-TK, whose specificity and efficiency were recognized in the previously reported paper, were used as a positive control, and Ad-CMV-LacZ was used as a negative control.

As a result, when compared with the positive control and the negative control, Ad-ribozymes showed specific trans-splicing and transgene induced, resulting in cell death.

16B and 16C show the results of MTS analysis in CAPAN-1 cells and HT-29 cells, respectively.

In the case of FIG. 16B as well, GCV was treated with 100uM, and Ad-ribozymes were M.O.I-dependently infected. As a result, specific cell death occurred in Ad-ribozymes. However, in Figure 16C wild-type Kras, HT-29 cells, except for positive viruses, it can be seen that no cell death occurs.

From these results, it can be seen that Ad-ribozymes recognized the specifically mutated Kras G12V and trans-spliced to induce the transgene.

Example 8: Ad - To ribozyme Confirmation of tumor regression in xenograft model by

1. Experimental animals

Specifically, male BALB/cAnNCrI nude mice (Orient Bio Inc.) of 4 to 5 weeks under pathogen-free conditions were used for the experiment. To make a xenograft mouse model, 8 mice were first injected with CAPAN-1 (1×10 ⁷ cells) intraperitoneally, and then tumors were generated 3 weeks later, and adenovirus ribozymes were administered 3 times (1×10 7 cells) at intervals of two days. ⁹ PFU). GCV (50mg/kg) was treated through the intraperitoneal cavity for 10 days, twice a day from the day after the first infection with the virus. And to make a wild-type Kras subcutaneous tumor model, a tumor model was produced using HT-29. 7 male BALB/c nude mice ^{were injected with 1×10 7} cells subcutaneously to generate tumors 2 weeks later. Ad-ribozyme was treated ^{intravenously with 1×10 9} cells 3 times at intervals of 2 days. GCV (50mg/kg) was observed after being treated intraperitoneally twice for 10 days.

2. Confirmation of tumor regression in xenograft models

In In order to confirm the specificity and efficiency of Ad-ribozyme in vivo, Ad-ribozymes identified through MTS analysis were infected with a xenograft mouse model transplanted with a human tumor.

Kras G12V mutated CAPAN-1 was injected with i,p to generate tumors, and Ad-ribozyme was treated (see Fig. 17A). Thereafter, GCV was treated to confirm whether the tumor was specifically regressed by Ad-ribozyme. The negative virus was infected with Ad-CMV-LacZ and the positive virus was infected with Ad-CMV-TK.

Compared to Ad-CMV-LacZ, Ad-CMV-TK and Ad-AS100KRib2-TK showed similar tumor regression in Kras G12V mutant tumors (P=0.467). In addition, a subcutaneous tumor mouse model was made with HT-29 expressing wild-type Kras.

17B is a graph showing the weight of the tumor by observing the tumor excluding necrosis by H&E staining.

Referring to Figure 17B, it can be seen that the weight of the tumor did not decrease Ad-ribozymes similar to the negative control group (P=0.5137). However, in the case of Ad-CMV-TK, which is a positive virus, it could be seen that the weight of the tumor decreased. In addition, comparing the results of Kras G12V mutated tumors and wild-type Kras tumors, it can be seen that Ad-ribozyme acts by specifically recognizing Kras G12V.

<110> INDUSTRY-ACADEMIC COOPERATION FOUNDATION, DANKOOK UNIVERSITY <120> TRANS-SPLICING GROUP I RIBOZYME SPECIFIC FOR KRAS G12V RNA <160> 44 <170> KopatentIn 1.71 <210> 1 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Kras wild primer <400> 1 gttggagctg gtggcgtagg c 21 <210> 2 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Kras 5'BamHI primer <400> 2 taatacgact cacta 15 <210> 3 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> kras rib T7-5' primer <400> 3 gggtaatacg actcactata ggaggtaaaa gttatcaggc atgc 44 <210> 4 <211> 44 <212> DNA <213> Artificial Sequence <220> <223> RY-PCR primer <400> 4 gggtaatacg actcactata gacagcaaaa gttatcaggc atgc 44 <210> 5 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> RY-RT primer <400> 5 tgtaaaacga cggccagtg 19 <210> 6 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> kras p1p10-rib1-5 primer <400> 6 cgatgatcac gaagacgcca aaaacata 28 <210> 7 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> kras p1p10-rib2-5 primer <400> 7 cgacatgatc acgaagacgc caaaaacata 30 <210> 8 <211> 37 <212> DNA <213> Artificial Sequence <220> <223> krib 3'primer <400> 8 aaggaaaaaa gcggccgctt attacaattt ggacttt 37 <210> 9 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> kras as 5'primer <400> 9 gggaagcttg caagagtgcc ttgacga 27 <210> 10 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> kras as 3'primer <400> 10 gggaaggctt ccatcaatta ctacttgc 28 <210> 11 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> kras as300 5'priemr <400> 11 gggtaatacg actcactata gggctactag gaccataggt a 41 <210> 12 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> kras t/s BamHI5' primer <400> 12 cgcggatcca ctgaatataa acttgtggta 30 <210> 13 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> cell t/s luci 3'nest primer <400> 13 cccaagcttg cccaacaccg gcataaag 28 <210> 14 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> TK 5'NruI 1set primer <400> 14 gtgatcatcg cgatgatcac gcttcgtacc cctgccat 38 <210> 15 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> TK 5'NruI 2setI primer <400> 15 gtgatcatcg cgacatgatc acgcttcgta cccctgccat 40 <210> 16 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> 3'TK BstBI primer <400> 16 aaggaaaaaa ttcgaattag cctcccccat 30 <210> 17 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> T7-R-Primer <400> 17 taatacgact cactataggg 20 <210> 18 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> IGS rev seq <400> 18 cctttcccgc aatttgacgg tctt 24 <210> 19 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> 5'TK stable primer <400> 19 cgggaattcg tggtaatgac aagc 24 <210> 20 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> 3'TK stable primer <400> 20 cggggatcca tccaggataa agacgtgcat ggg 33 <210> 21 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> 5'LITR EcoRI primer <400> 21 ggaattctgg agtttgtgac gtggcg 26 <210> 22 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> 3'LITR XbaI primer <400> 22 gctctagatg gccaaatctt actcggttac gc 32 <210> 23 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> 5'viral LacZ primer <400> 23 ggaattcatg gtcgttttac aacgtcgtg 29 <210> 24 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> cancer.lacZ-3 primer <400> 24 gggaagcttc ggattgaccg taatggga 28 <210> 25 <211> 513 <212> RNA <213> Artificial Sequence <220> <223> AS100KRib1 <400> 25 aagcuuccau caauuacuac uugcuuccug uaggaauccu cuauuguugg aucauauucg 60 uccacaaaau gauucugaau uagcuguauc gucaaggcac ucuugcaagc uucauuauca 120 gcagcuaaaa guuaucaggc augcaccugg uagcuagucu uuaaaccaau agauugcauc 180 gguuuaaaag gcaagaccgu caaauugcgg gaaagggguc aacagccguu caguaccaag 240 ucucagggga aacuuugaga uggccuugca aaggguaugg uaauaagcug acggacaugg 300 uccuaaccac gcagccaagu ccuaagucaa cagaucuucu guugauaugg augcaguuca 360 cagacuaaau gucggucggg gaagauguau ucuucucaua agauauaguc ggaccucucc 420 uuaaugggag cuagcggaug aagugaugca acacuggagc cgcugggaac uaauuuguau 480 gcgaaaguau auugauuagu uuuggaguac ucg 513 <210> 26 <211> 713 <212> RNA <213> Artificial Sequence <220> <223> AS300KRib1 <400> 26 aagcuucuac uaggaccaua gguacaucuu cagaguccuu aacucuuuua auuuguucuc 60 uauaauggug aauaucuuca aaugauuuag uauuauuuau ggcaaauaca caaagaaagc 120 ccuccccagu ccucauguac uggucccuca uugcacugua cuccucuuga ccugcugugu 180 cgagaauauc caagagacag guuucuccau caauuacuac uugcuuccug uaggaauccu 240 cuauuguugg aucauauucg uccacaaaau gauucugaau uagcuguauc gucaaggcac 300 ucuugcaagc uucauuauca gcagcuaaaa guuaucaggc augcaccugg uagcuagucu 360 uuaaaccaau agauugcauc gguuuaaaag gcaagaccgu caaauugcgg gaaagggguc 420 aacagccguu caguaccaag ucucagggga aacuuugaga uggccuugca aaggguaugg 480 uaauaagcug acggacaugg uccuaaccac gcagccaagu ccuaagucaa cagaucuucu 540 guugauaugg augcaguuca cagacuaaau gucggucggg gaagauguau ucuucucaua 600 agauauaguc ggaccucucc uuaaugggag cuagcggaug aagugaugca acacuggagc 660 cgcugggaac uaauuuguau gcgaaaguau auugauuagu uuuggaguac ucg 713 <210> 27 <211> 515 <212> RNA <213> Artificial Sequence <220> <223> AS100KRib2 <400> 27 aagcuuccau caauuacuac uugcuuccug uaggaauccu cuauuguugg aucauauucg 60 uccacaaaau gauucugaau uagcuguauc gucaaggcac ucuugcaagc uucaucaugg 120 ccgacagcaa aaguuaucag gcaugcaccu gguagcuagu cuuuaaacca auagauugca 180 ucgguuuaaa aggcaagacc gucaaauugc gggaaagggg ucaacagccg uucaguacca 240 agucucaggg gaaacuuuga gauggccuug caaaggguau gguaauaagc ugacggacau 300 gguccuaacc acgcagccaa guccuaaguc aacagaucuu cuguugauau ggaugcaguu 360 cacagacuaa augucggucg gggaagaugu auucuucuca uaagauauag ucggaccucu 420 ccuuaauggg agcuagcgga ugaagugaug caacacugga gccgcuggga acuaauuugu 480 augcgaaagu auauugauua guuuuggagu acucg 515 <210> 28 <211> 715 <212> RNA <213> Artificial Sequence <220> <223> AS300KRib2 <400> 28 aagcuucuac uaggaccaua gguacaucuu cagaguccuu aacucuuuua auuuguucuc 60 uauaauggug aauaucuuca aaugauuuag uauuauuuau ggcaaauaca caaagaaagc 120 ccuccccagu ccucauguac uggucccuca uugcacugua cuccucuuga ccugcugugu 180 cgagaauauc caagagacag guuucuccau caauuacuac uugcuuccug uaggaauccu 240 cuauuguugg aucauauucg uccacaaaau gauucugaau uagcuguauc gucaaggcac 300 ucuugcaagc uucaucaugg ccgacagcaa aaguuaucag gcaugcaccu gguagcuagu 360 cuuuaaacca auagauugca ucgguuuaaa aggcaagacc gucaaauugc gggaaagggg 420 ucaacagccg uucaguacca agucucaggg gaaacuuuga gauggccuug caaaggguau 480 gguaauaagc ugacggacau gguccuaacc acgcagccaa guccuaaguc aacagaucuu 540 cuguugauau ggaugcaguu cacagacuaa augucggucg gggaagaugu auucuucuca 600 uaagauauag ucggaccucu ccuuaauggg agcuagcgga ugaagugaug caacacugga 660 gccgcuggga acuaauuugu augcgaaagu auauugauua guuuuggagu acucg 715 <210> 29 <211> 2184 <212> DNA <213> Artificial Sequence <220> <223> AS100KRib1-F.luci <400> 29 aagcttccat caattactac ttgcttcctg taggaatcct ctattgttgg atcatattcg 60 tccacaaaat gattctgaat tagctgtatc gtcaaggcac tcttgcaagc ttcattatca 120 gcagctaaaa gttatcaggc atgcacctgg tagctagtct ttaaaccaat agattgcatc 180 ggtttaaaag gcaagaccgt caaattgcgg gaaaggggtc aacagccgtt cagtaccaag 240 tctcagggga aactttgaga tggccttgca aagggtatgg taataagctg acggacatgg 300 tcctaaccac gcagccaagt cctaagtcaa cagatcttct gttgatatgg atgcagttca 360 cagactaaat gtcggtcggg gaagatgtat tcttctcata agatatagtc ggacctctcc 420 ttaatgggag ctagcggatg aagtgatgca acactggagc cgctgggaac taatttgtat 480 gcgaaagtat attgattagt tttggagtac tcgcgatgat cacgaagacg ccaaaaacat 540 aaagaaaggc ccggcgccat tctatcctct agaggatgga accgctggag agcaactgca 600 taaggctatg aagagatacg ccctggttcc tggaacaatt gcttttacag atgcacatat 660 cgaggtgaac atcacgtacg cggaatactt cgaaatgtcc gttcggttgg cagaagctat 720 gaaacgatat gggctgaata caaatcacag aatcgtcgta tgcagtgaaa actctcttca 780 attctttatg ccggtgttgg gcgcgttatt tatcggagtt gcagttgcgc ccgcgaacga 840 catttataat gaacgtgaat tgctcaacag tatgaacatt tcgcagccta ccgtagtgtt 900 tgtttccaaa aaggggttgc aaaaaatttt gaacgtgcaa aaaaaattac caataatcca 960 gaaaattatt atcatggatt ctaaaacgga ttaccaggga tttcagtcga tgtacacgtt 1020 cgtcacatct catctacctc ccggttttaa tgaatacgat tttgtaccag agtcctttga 1080 tcgtgacaaa acaattgcac tgataatgaa ttcctctgga tctactgggt tacctaaggg 1140 tgtggccctt ccgcatagaa ctgcctgcgt cagattctcg catgccagag atcctatttt 1200 tggcaatcaa atcattccgg atactgcgat tttaagtgtt gttccattcc atcacggttt 1260 tggaatgttt actacactcg gatatttgat atgtggattt cgagtcgtct taatgtatag 1320 atttgaagaa gagctgtttt tacgatccct tcaggattac aaaattcaaa gtgcgttgct 1380 agtaccaacc ctattttcat tcttcgccaa aagcactctg attgacaaat acgatttatc 1440 taatttacac gaaattgctt ctgggggcgc acctctttcg aaagaagtcg gggaagcggt 1500 tgcaaaacgc ttccatcttc cagggatacg acaaggatat gggctcactg agactacatc 1560 agctattctg attacacccg agggggatga taaaccgggc gcggtcggta aagttgttcc 1620 attttttgaa gcgaaggttg tggatctgga taccgggaaa acgctgggcg ttaatcagag 1680 aggcgaatta tgtgtcagag gacctatgat tatgtccggt tatgtaaaca atccggaagc 1740 gaccaacgcc ttgattgaca aggatggatg gctacattct ggagacatag cttactggga 1800 cgaagacgaa cacttcttca tagttgaccg cttgaagtct ttaattaaat acaaaggata 1860 tcaggtggcc cccgctgaat tggaatcgat attgttacaa caccccaaca tcttcgacgc 1920 gggcgtggca ggtcttcccg acgatgacgc cggtgaactt cccgccgccg ttgttgtttt 1980 ggagcacgga aagacgatga cggaaaaaga gatcgtggat tacgtggcca gtcaagtaac 2040 aaccgcgaaa aagttgcgcg gaggagttgt gtttgtggac gaagtaccga aaggtcttac 2100 cggaaaactc gacgcaagaa aaatcagaga gatcctcata aaggccaaga agggcggaaa 2160 gtccaaattg taataagcgg ccgc 2184 <210> 30 <211> 2384 <212> DNA <213> Artificial Sequence <220> <223> AS300KRib1-F.luci <400> 30 aagcttctac taggaccata ggtacatctt cagagtcctt aactctttta atttgttctc 60 tataatggtg aatatcttca aatgatttag tattatttat ggcaaataca caaagaaagc 120 cctccccagt cctcatgtac tggtccctca ttgcactgta ctcctcttga cctgctgtgt 180 cgagaatatc caagagacag gtttctccat caattactac ttgcttcctg taggaatcct 240 ctattgttgg atcatattcg tccacaaaat gattctgaat tagctgtatc gtcaaggcac 300 tcttgcaagc ttcattatca gcagctaaaa gttatcaggc atgcacctgg tagctagtct 360 ttaaaccaat agattgcatc ggtttaaaag gcaagaccgt caaattgcgg gaaaggggtc 420 aacagccgtt cagtaccaag tctcagggga aactttgaga tggccttgca aagggtatgg 480 taataagctg acggacatgg tcctaaccac gcagccaagt cctaagtcaa cagatcttct 540 gttgatatgg atgcagttca cagactaaat gtcggtcggg gaagatgtat tcttctcata 600 agatatagtc ggacctctcc ttaatgggag ctagcggatg aagtgatgca acactggagc 660 cgctgggaac taatttgtat gcgaaagtat attgattagt tttggagtac tcgcgatgat 720 cacgaagacg ccaaaaacat aaagaaaggc ccggcgccat tctatcctct agaggatgga 780 accgctggag agcaactgca taaggctatg aagagatacg ccctggttcc tggaacaatt 840 gcttttacag atgcacatat cgaggtgaac atcacgtacg cggaatactt cgaaatgtcc 900 gttcggttgg cagaagctat gaaacgatat gggctgaata caaatcacag aatcgtcgta 960 tgcagtgaaa actctcttca attctttatg ccggtgttgg gcgcgttatt tatcggagtt 1020 gcagttgcgc ccgcgaacga catttataat gaacgtgaat tgctcaacag tatgaacatt 1080 tcgcagccta ccgtagtgtt tgtttccaaa aaggggttgc aaaaaatttt gaacgtgcaa 1140 aaaaaattac caataatcca gaaaattatt atcatggatt ctaaaacgga ttaccaggga 1200 tttcagtcga tgtacacgtt cgtcacatct catctacctc ccggttttaa tgaatacgat 1260 tttgtaccag agtcctttga tcgtgacaaa acaattgcac tgataatgaa ttcctctgga 1320 tctactgggt tacctaaggg tgtggccctt ccgcatagaa ctgcctgcgt cagattctcg 1380 catgccagag atcctatttt tggcaatcaa atcattccgg atactgcgat tttaagtgtt 1440 gttccattcc atcacggttt tggaatgttt actacactcg gatatttgat atgtggattt 1500 cgagtcgtct taatgtatag atttgaagaa gagctgtttt tacgatccct tcaggattac 1560 aaaattcaaa gtgcgttgct agtaccaacc ctattttcat tcttcgccaa aagcactctg 1620 attgacaaat acgatttatc taatttacac gaaattgctt ctgggggcgc acctctttcg 1680 aaagaagtcg gggaagcggt tgcaaaacgc ttccatcttc cagggatacg acaaggatat 1740 gggctcactg agactacatc agctattctg attacacccg agggggatga taaaccgggc 1800 gcggtcggta aagttgttcc attttttgaa gcgaaggttg tggatctgga taccgggaaa 1860 acgctgggcg ttaatcagag aggcgaatta tgtgtcagag gacctatgat tatgtccggt 1920 tatgtaaaca atccggaagc gaccaacgcc ttgattgaca aggatggatg gctacattct 1980 ggagacatag cttactggga cgaagacgaa cacttcttca tagttgaccg cttgaagtct 2040 ttaattaaat acaaaggata tcaggtggcc cccgctgaat tggaatcgat attgttacaa 2100 caccccaaca tcttcgacgc gggcgtggca ggtcttcccg acgatgacgc cggtgaactt 2160 cccgccgccg ttgttgtttt ggagcacgga aagacgatga cggaaaaaga gatcgtggat 2220 tacgtggcca gtcaagtaac aaccgcgaaa aagttgcgcg gaggagttgt gtttgtggac 2280 gaagtaccga aaggtcttac cggaaaactc gacgcaagaa aaatcagaga gatcctcata 2340 aaggccaaga agggcggaaa gtccaaattg taataagcgg ccgc 2384 <210> 31 <211> 2188 <212> DNA <213> Artificial Sequence <220> <223> AS100KRib2-F.luci <400> 31 aagcttccat caattactac ttgcttcctg taggaatcct ctattgttgg atcatattcg 60 tccacaaaat gattctgaat tagctgtatc gtcaaggcac tcttgcaagc ttcatcatgg 120 ccgacagcaa aagttatcag gcatgcacct ggtagctagt ctttaaacca atagattgca 180 tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg tcaacagccg ttcagtacca 240 agtctcaggg gaaactttga gatggccttg caaagggtat ggtaataagc tgacggacat 300 ggtcctaacc acgcagccaa gtcctaagtc aacagatctt ctgttgatat ggatgcagtt 360 cacagactaa atgtcggtcg gggaagatgt attcttctca taagatatag tcggacctct 420 ccttaatggg agctagcgga tgaagtgatg caacactgga gccgctggga actaatttgt 480 atgcgaaagt atattgatta gttttggagt actcgcgaca tgatcacgaa gacgccaaaa 540 acataaagaa aggcccggcg ccattctatc ctctagagga tggaaccgct ggagagcaac 600 tgcataaggc tatgaagaga tacgccctgg ttcctggaac aattgctttt acagatgcac 660 atatcgaggt gaacatcacg tacgcggaat acttcgaaat gtccgttcgg ttggcagaag 720 ctatgaaacg atatgggctg aatacaaatc acagaatcgt cgtatgcagt gaaaactctc 780 ttcaattctt tatgccggtg ttgggcgcgt tatttatcgg agttgcagtt gcgcccgcga 840 acgacattta taatgaacgt gaattgctca acagtatgaa catttcgcag cctaccgtag 900 tgtttgtttc caaaaagggg ttgcaaaaaa ttttgaacgt gcaaaaaaaa ttaccaataa 960 tccagaaaat tattatcatg gattctaaaa cggattacca gggatttcag tcgatgtaca 1020 cgttcgtcac atctcatcta cctcccggtt ttaatgaata cgattttgta ccagagtcct 1080 ttgatcgtga caaaacaatt gcactgataa tgaattcctc tggatctact gggttaccta 1140 agggtgtggc ccttccgcat agaactgcct gcgtcagatt ctcgcatgcc agagatccta 1200 tttttggcaa tcaaatcatt ccggatactg cgattttaag tgttgttcca ttccatcacg 1260 gttttggaat gtttactaca ctcggatatt tgatatgtgg atttcgagtc gtcttaatgt 1320 atagatttga agaagagctg tttttacgat cccttcagga ttacaaaatt caaagtgcgt 1380 tgctagtacc aaccctattt tcattcttcg ccaaaagcac tctgattgac aaatacgatt 1440 tatctaattt acacgaaatt gcttctgggg gcgcacctct ttcgaaagaa gtcggggaag 1500 cggttgcaaa acgcttccat cttccaggga tacgacaagg atatgggctc actgagacta 1560 catcagctat tctgattaca cccgaggggg atgataaacc gggcgcggtc ggtaaagttg 1620 ttccattttt tgaagcgaag gttgtggatc tggataccgg gaaaacgctg ggcgttaatc 1680 agagaggcga attatgtgtc agaggaccta tgattatgtc cggttatgta aacaatccgg 1740 aagcgaccaa cgccttgatt gacaaggatg gatggctaca ttctggagac atagcttact 1800 gggacgaaga cgaacacttc ttcatagttg accgcttgaa gtctttaatt aaatacaaag 1860 gatatcaggt ggcccccgct gaattggaat cgatattgtt acaacacccc aacatcttcg 1920 acgcgggcgt ggcaggtctt cccgacgatg acgccggtga acttcccgcc gccgttgttg 1980 ttttggagca cggaaagacg atgacggaaa aagagatcgt ggattacgtg gccagtcaag 2040 taacaaccgc gaaaaagttg cgcggaggag ttgtgtttgt ggacgaagta ccgaaaggtc 2100 ttaccggaaa actcgacgca agaaaaatca gagagatcct cataaaggcc aagaagggcg 2160 gaaagtccaa attgtaataa gcggccgc 2188 <210> 32 <211> 2377 <212> DNA <213> Artificial Sequence <220> <223> AS300KRib2-F.luci <400> 32 aagcttctac taggaccata ggtacatctt cagagtcctt aactctttta atttgttctc 60 tataatggtg aatatcttca aatgatttag tattatttat ggcaaataca caaagaaagc 120 cctccccagt cctcatgtac tggtccctca ttgcactgta ctcctcttga cctgctgtgt 180 cgagaatatc caagagacag gtttctccat caattactac ttgcttcctg taggaatcct 240 ctattgttgg atcatattcg tccacaaaat gattctgaat tagctgtatc gtcaaggcac 300 tcttgcaagc ttcatcatgg ccgacagcaa aagttatcag gcatgcacct ggtagctagt 360 ctttaaacca atagattgca tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg 420 tcaacagccg ttcagtacca agtctcaggg gaaactttga gatggccttg caaagggtat 480 ggtaataagc tgacggacat ggtcctaacc acgcagccaa gtcctaagtc aacagatctt 540 ctgttgatat ggatgcagtt cacagactaa atgtcggtcg gggaagatgt attcttctca 600 taagatatag tcggacctct ccttaatggg agctagcgga tgaagtgatg caacactgga 660 gccgctggga actaatttgt atgcgaaagt atattgatta gttttggagt actcgcgaca 720 tgatcacgaa gacgccaaaa acataaagaa aggcccggcg ccattctatc ctctagagga 780 tggaaccgct ggagagcaac tgcataaggc tatgaagaga tacgccctgg ttcctggaac 840 aattgctttt acagatgcac atatcgaggt gaacatcacg tacgcggaat acttcgaaat 900 gtccgttcgg ttggcagaag ctatgaaacg atatgggctg aatacaaatc acagaatcgt 960 cgtatgcagt gaaaactctc ttcaattctt tatgccggtg ttgggcgcgt tatttatcgg 1020 agttgcagtt gcgcccgcga acgacattta taatgaacgt gaattgctca acagtatgaa 1080 catttcgcag cctaccgtag tgtttgtttc caaaaagggg ttgcaaaaaa ttttgaacgt 1140 gcaaaaaaaa ttaccaataa tccagaaaat tattatcatg gattctaaaa cggattacca 1200 gggatttcag tcgatgtaca cgttcgtcac atctcatcta cctcccggtt ttaatgaata 1260 cgattttgta ccagagtcct ttgatcgtga caaaacaatt gcactgataa tgaattcctc 1320 tggatctact gggttaccta agggtgtggc ccttccgcat agaactgcct gcgtcagatt 1380 ctcgcatgcc agagatccta tttttggcaa tcaaatcatt ccggatactg cgattttaag 1440 tgttgttcca ttccatcacg gttttggaat gtttactaca ctcggatatt tgatatgtgg 1500 atttcgagtc gtcttaatgt atagatttga agaagagctg tttttacgat cccttcagga 1560 ttacaaaatt caaagtgcgt tgctagtacc aaccctattt tcattcttcg ccaaaagcac 1620 tctgattgac aaatacgatt tatctaattt acacgaaatt gcttctgggg gcgcacctct 1680 ttcgaaagaa gtcggggaag cggttgcaaa acgcttccat cttccaggga tacgacaagg 1740 atatgggctc actgagacta catcagctat tctgattaca cccgaggggg atgataaacc 1800 gggcgcggtc ggtaaagttg ttccattttt tgaagcgaag gttgtggatc tggataccgg 1860 gaaaacgctg ggcgttaatc agagaggcga attatgtgtc agaggaccta tgattatgtc 1920 cggttatgta aacaatccgg aagcgaccaa cgccttgatt gacaaggatg gatggctaca 1980 ttctggagac atagcttact gggacgaaga cgaacacttc ttcatagttg accgcttgaa 2040 gtctttaatt aaatacaaag gatatcaggt ggcccccgct gaattggaat cgatattgtt 2100 acaacacccc aacatcttcg acgcgggcgt ggcaggtctt cccgacgatg acgccggtga 2160 acttcccgcc gccgttgttg ttttggagca cggaaagacg atgacggaaa aagagatcgt 2220 ggattacgtg gccagtcaag taacaaccgc gaaaaagttg cgcggaggag ttgtgtttgt 2280 ggacgaagta ccgaaaggtc ttaccggaaa actcgacgca agaaaaatca gagagatcct 2340 cataaaggcc aagaagggcg gaaagtccaa attgtaa 2377 <210> 33 <211> 1650 <212> DNA <213> Artificial Sequence <220> <223> AS100KRib1-TK <400> 33 aagcttccat caattactac ttgcttcctg taggaatcct ctattgttgg atcatattcg 60 tccacaaaat gattctgaat tagctgtatc gtcaaggcac tcttgcaagc ttcattatca 120 gcagctaaaa gttatcaggc atgcacctgg tagctagtct ttaaaccaat agattgcatc 180 ggtttaaaag gcaagaccgt caaattgcgg gaaaggggtc aacagccgtt cagtaccaag 240 tctcagggga aactttgaga tggccttgca aagggtatgg taataagctg acggacatgg 300 tcctaaccac gcagccaagt cctaagtcaa cagatcttct gttgatatgg atgcagttca 360 cagactaaat gtcggtcggg gaagatgtat tcttctcata agatatagtc ggacctctcc 420 ttaatgggag ctagcggatg aagtgatgca acactggagc cgctgggaac taatttgtat 480 gcgaaagtat attgattagt tttggagtac tcgcgatgat cacgcttcgt acccctgcca 540 tcaacacgcg tctgcgttcg accaggctgc gcgttctcgc ggccatagca accgacgtac 600 ggcgttgcgc cctcgccggc agcaagaagc cacggaagtc cgcctggagc agaaaatgcc 660 cacgctactg cgggtttata tagacggtcc tcacgggatg gggaaaacca ccaccacgca 720 actgctggtg gccctgggtt cgcgcgacga tatcgtctac gtacccgagc cgatgactta 780 ctggcaggtg ctgggggctt ccgagacaat cgcgaacatc tacaccacac aacaccgcct 840 cgaccagggt gagatatcgg ccggggacgc ggcggtggta atgacaagcg cccagataac 900 aatgggcatg ccttatgccg tgaccgacgc cgttctggct cctcatgtcg ggggggaggc 960 tgggagttca catgccccgc ccccggccct caccctcatc ttcgaccgcc atcccatcgc 1020 cgccctcctg tgctacccgg ccgcgcgata ccttatgggc agcatgaccc cccaggccgt 1080 gctggcgttc gtggccctca tcccgccgac cttgcccggc acaaacatcg tgttgggggc 1140 ccttccggag gacagacaca tcgaccgcct ggccaaacgc cagcgccccg gcgagcggct 1200 tgacctggct atgctggccg cgattcgccg cgtttacggg ctgcttgcca atacggtgcg 1260 gtatctgcag ggcggcgggt cgtggtggga ggattgggga cagctttcgg ggacggccgt 1320 gccgccccag ggtgccgagc cccagagcaa cgcgggccca cgaccccata tcggggacac 1380 gttatttacc ctgtttcggg cccccgagtt gctggccccc aacggcgacc tgtataacgt 1440 gtttgcctgg gccttggacg tcttggccaa acgcctccgt cccatgcacg tctttatcct 1500 ggattacgac caatcgcccg ccggctgccg ggacgccctg ctgcaactta cctccgggat 1560 ggtccagacc cacgtcacca ccccaggctc cataccgacg atctgcgacc tggcgcgcac 1620 gtttgcccgg gagatggggg aggctaataa 1650 <210> 34 <211> 1850 <212> DNA <213> Artificial Sequence <220> <223> AS300KRib1-TK <400> 34 aagcttctac taggaccata ggtacatctt cagagtcctt aactctttta atttgttctc 60 tataatggtg aatatcttca aatgatttag tattatttat ggcaaataca caaagaaagc 120 cctccccagt cctcatgtac tggtccctca ttgcactgta ctcctcttga cctgctgtgt 180 cgagaatatc caagagacag gtttctccat caattactac ttgcttcctg taggaatcct 240 ctattgttgg atcatattcg tccacaaaat gattctgaat tagctgtatc gtcaaggcac 300 tcttgcaagc ttcattatca gcagctaaaa gttatcaggc atgcacctgg tagctagtct 360 ttaaaccaat agattgcatc ggtttaaaag gcaagaccgt caaattgcgg gaaaggggtc 420 aacagccgtt cagtaccaag tctcagggga aactttgaga tggccttgca aagggtatgg 480 taataagctg acggacatgg tcctaaccac gcagccaagt cctaagtcaa cagatcttct 540 gttgatatgg atgcagttca cagactaaat gtcggtcggg gaagatgtat tcttctcata 600 agatatagtc ggacctctcc ttaatgggag ctagcggatg aagtgatgca acactggagc 660 cgctgggaac taatttgtat gcgaaagtat attgattagt tttggagtac tcgcgatgat 720 cacgcttcgt acccctgcca tcaacacgcg tctgcgttcg accaggctgc gcgttctcgc 780 ggccatagca accgacgtac ggcgttgcgc cctcgccggc agcaagaagc cacggaagtc 840 cgcctggagc agaaaatgcc cacgctactg cgggtttata tagacggtcc tcacgggatg 900 gggaaaacca ccaccacgca actgctggtg gccctgggtt cgcgcgacga tatcgtctac 960 gtacccgagc cgatgactta ctggcaggtg ctgggggctt ccgagacaat cgcgaacatc 1020 tacaccacac aacaccgcct cgaccagggt gagatatcgg ccggggacgc ggcggtggta 1080 atgacaagcg cccagataac aatgggcatg ccttatgccg tgaccgacgc cgttctggct 1140 cctcatgtcg ggggggaggc tgggagttca catgccccgc ccccggccct caccctcatc 1200 ttcgaccgcc atcccatcgc cgccctcctg tgctacccgg ccgcgcgata ccttatgggc 1260 agcatgaccc cccaggccgt gctggcgttc gtggccctca tcccgccgac cttgcccggc 1320 acaaacatcg tgttgggggc ccttccggag gacagacaca tcgaccgcct ggccaaacgc 1380 cagcgccccg gcgagcggct tgacctggct atgctggccg cgattcgccg cgtttacggg 1440 ctgcttgcca atacggtgcg gtatctgcag ggcggcgggt cgtggtggga ggattgggga 1500 cagctttcgg ggacggccgt gccgccccag ggtgccgagc cccagagcaa cgcgggccca 1560 cgaccccata tcggggacac gttatttacc ctgtttcggg cccccgagtt gctggccccc 1620 aacggcgacc tgtataacgt gtttgcctgg gccttggacg tcttggccaa acgcctccgt 1680 cccatgcacg tctttatcct ggattacgac caatcgcccg ccggctgccg ggacgccctg 1740 ctgcaactta cctccgggat ggtccagacc cacgtcacca ccccaggctc cataccgacg 1800 atctgcgacc tggcgcgcac gtttgcccgg gagatggggg aggctaataa 1850 <210> 35 <211> 1654 <212> DNA <213> Artificial Sequence <220> <223> AS100KRib2-TK <400> 35 aagcttccat caattactac ttgcttcctg taggaatcct ctattgttgg atcatattcg 60 tccacaaaat gattctgaat tagctgtatc gtcaaggcac tcttgcaagc ttcatcatgg 120 ccgacagcaa aagttatcag gcatgcacct ggtagctagt ctttaaacca atagattgca 180 tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg tcaacagccg ttcagtacca 240 agtctcaggg gaaactttga gatggccttg caaagggtat ggtaataagc tgacggacat 300 ggtcctaacc acgcagccaa gtcctaagtc aacagatctt ctgttgatat ggatgcagtt 360 cacagactaa atgtcggtcg gggaagatgt attcttctca taagatatag tcggacctct 420 ccttaatggg agctagcgga tgaagtgatg caacactgga gccgctggga actaatttgt 480 atgcgaaagt atattgatta gttttggagt actcgcgaca tgatcacgct tcgtacccct 540 gccatcaaca cgcgtctgcg ttcgaccagg ctgcgcgttc tcgcggccat agcaaccgac 600 gtacggcgtt gcgccctcgc cggcagcaag aagccacgga agtccgcctg gagcagaaaa 660 tgcccacgct actgcgggtt tatatagacg gtcctcacgg gatggggaaa accaccacca 720 cgcaactgct ggtggccctg ggttcgcgcg acgatatcgt ctacgtaccc gagccgatga 780 cttactggca ggtgctgggg gcttccgaga caatcgcgaa catctacacc acacaacacc 840 gcctcgacca gggtgagata tcggccgggg acgcggcggt ggtaatgaca agcgcccaga 900 taacaatggg catgccttat gccgtgaccg acgccgttct ggctcctcat gtcggggggg 960 aggctgggag ttcacatgcc ccgcccccgg ccctcaccct catcttcgac cgccatccca 1020 tcgccgccct cctgtgctac ccggccgcgc gataccttat gggcagcatg accccccagg 1080 ccgtgctggc gttcgtggcc ctcatcccgc cgaccttgcc cggcacaaac atcgtgttgg 1140 gggcccttcc ggaggacaga cacatcgacc gcctggccaa acgccagcgc cccggcgagc 1200 ggcttgacct ggctatgctg gccgcgattc gccgcgttta cgggctgctt gccaatacgg 1260 tgcggtatct gcagggcggc gggtcgtggt gggaggattg gggacagctt tcggggacgg 1320 ccgtgccgcc ccagggtgcc gagccccaga gcaacgcggg cccacgaccc catatcgggg 1380 acacgttatt taccctgttt cgggcccccg agttgctggc ccccaacggc gacctgtata 1440 acgtgtttgc ctgggccttg gacgtcttgg ccaaacgcct ccgtcccatg cacgtcttta 1500 tcctggatta cgaccaatcg cccgccggct gccgggacgc cctgctgcaa cttacctccg 1560 ggatggtcca gacccacgtc accaccccag gctccatacc gacgatctgc gacctggcgc 1620 gcacgtttgc ccgggagatg ggggaggcta ataa 1654 <210> 36 <211> 1854 <212> DNA <213> Artificial Sequence <220> <223> AS300KRib2-TK <400> 36 aagcttctac taggaccata ggtacatctt cagagtcctt aactctttta atttgttctc 60 tataatggtg aatatcttca aatgatttag tattatttat ggcaaataca caaagaaagc 120 cctccccagt cctcatgtac tggtccctca ttgcactgta ctcctcttga cctgctgtgt 180 cgagaatatc caagagacag gtttctccat caattactac ttgcttcctg taggaatcct 240 ctattgttgg atcatattcg tccacaaaat gattctgaat tagctgtatc gtcaaggcac 300 tcttgcaagc ttcatcatgg ccgacagcaa aagttatcag gcatgcacct ggtagctagt 360 ctttaaacca atagattgca tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg 420 tcaacagccg ttcagtacca agtctcaggg gaaactttga gatggccttg caaagggtat 480 ggtaataagc tgacggacat ggtcctaacc acgcagccaa gtcctaagtc aacagatctt 540 ctgttgatat ggatgcagtt cacagactaa atgtcggtcg gggaagatgt attcttctca 600 taagatatag tcggacctct ccttaatggg agctagcgga tgaagtgatg caacactgga 660 gccgctggga actaatttgt atgcgaaagt atattgatta gttttggagt actcgcgaca 720 tgatcacgct tcgtacccct gccatcaaca cgcgtctgcg ttcgaccagg ctgcgcgttc 780 tcgcggccat agcaaccgac gtacggcgtt gcgccctcgc cggcagcaag aagccacgga 840 agtccgcctg gagcagaaaa tgcccacgct actgcgggtt tatatagacg gtcctcacgg 900 gatggggaaa accaccacca cgcaactgct ggtggccctg ggttcgcgcg acgatatcgt 960 ctacgtaccc gagccgatga cttactggca ggtgctgggg gcttccgaga caatcgcgaa 1020 catctacacc acacaacacc gcctcgacca gggtgagata tcggccgggg acgcggcggt 1080 ggtaatgaca agcgcccaga taacaatggg catgccttat gccgtgaccg acgccgttct 1140 ggctcctcat gtcggggggg aggctgggag ttcacatgcc ccgcccccgg ccctcaccct 1200 catcttcgac cgccatccca tcgccgccct cctgtgctac ccggccgcgc gataccttat 1260 gggcagcatg accccccagg ccgtgctggc gttcgtggcc ctcatcccgc cgaccttgcc 1320 cggcacaaac atcgtgttgg gggcccttcc ggaggacaga cacatcgacc gcctggccaa 1380 acgccagcgc cccggcgagc ggcttgacct ggctatgctg gccgcgattc gccgcgttta 1440 cgggctgctt gccaatacgg tgcggtatct gcagggcggc gggtcgtggt gggaggattg 1500 gggacagctt tcggggacgg ccgtgccgcc ccagggtgcc gagccccaga gcaacgcggg 1560 cccacgaccc catatcgggg acacgttatt taccctgttt cgggcccccg agttgctggc 1620 ccccaacggc gacctgtata acgtgtttgc ctgggccttg gacgtcttgg ccaaacgcct 1680 ccgtcccatg cacgtcttta tcctggatta cgaccaatcg cccgccggct gccgggacgc 1740 cctgctgcaa cttacctccg ggatggtcca gacccacgtc accaccccag gctccatacc 1800 gacgatctgc gacctggcgc gcacgtttgc ccgggagatg ggggaggcta ataa 1854 <210> 37 <211> 8793 <212> DNA <213> Artificial Sequence <220> <223> pAVQ-AS300KRib1 <400> 37 taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60 agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120 tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180 ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240 tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatcccta ctaggaccat aggtacatct tcagagtcct taactctttt 1680 aatttgttct ctataatggt gaatatcttc aaatgattta gtattattta tggcaaatac 1740 acaaagaaag ccctccccag tcctcatgta ctggtccctc attgcactgt actcctcttg 1800 acctgctgtg tcgagaatat ccaagagaca ggtttctcca tcaattacta cttgcttcct 1860 gtaggaatcc tctattgttg gatcatattc gtccacaaaa tgattctgaa ttagctgtat 1920 cgtcaaggca ctcttgcaag cttcattatc agcagctaaa agttatcagg catgcacctg 1980 gtagctagtc tttaaaccaa tagattgcat cggtttaaaa ggcaagaccg tcaaattgcg 2040 ggaaaggggt caacagccgt tcagtaccaa gtctcagggg aaactttgag atggccttgc 2100 aaagggtatg gtaataagct gacggacatg gtcctaacca cgcagccaag tcctaagtca 2160 acagatcttc tgttgatatg gatgcagttc acagactaaa tgtcggtcgg ggaagatgta 2220 ttcttctcat aagatatagt cggacctctc cttaatggga gctagcggat gaagtgatgc 2280 aacactggag ccgctgggaa ctaatttgta tgcgaaagta tattgattag ttttggagta 2340 ctccgaaaga tcccaacgaa aagagagacc acatggtcct tcttgagttt gtaacagctg 2400 ctgggattac acatggcatg gatgaactgt acaactgagg atcccccgac ctcgacctct 2460 ggctaataaa ggaaatttat tttcattgca atagtgtgtt ggaatttttt gtgtctctca 2520 ctcggaagga catatgggag ggcaaatcat ttggtcgaga tccctcggag atcggatctg 2580 ggcgtggtta agggtgggaa agaatatata aggtgggggt cttatgtagt tttgtatctg 2640 ttttgcagca gccgccgccg ccatgagcac caactcgttt gatggaagca ttgtgagctc 2700 atatttgaca acgcgcatgc ccccatgggc cggggtgcgt cagaatgtga tgggctccag 2760 cattgatggt cgccccgtcc tgcccgcaaa ctctactacc ttgacctacg agaccgtgtc 2820 tggaacgccg ttggagactg cagcctccgc cgccgcttca gccgctgcag ccaccgcccg 2880 cgggattgtg actgactttg ctttcctgag cccgcttgca agcagtgcag cttcccgttc 2940 atccgcccgc gatgacaagt tgacggctct tttggcacaa ttggattctt tgacccggga 3000 acttaatgtc gtttctcagc agctgttgga tctgcgccag caggtttctg ccctgaaggc 3060 ttcctcccct cccaatgcgg tttaaaacat aaataaaaaa ccagactctg tttggatttg 3120 gatcaagcaa gtgtcttgct gtctttattt aggggttttg cgcgcgcggt aggcccggga 3180 ccagcggtct cggtcgttga gggtcctgtg tattttttcc aggacgtggt aaaggtgact 3240 ctggatgttc agatacatgg gcataagccc gtctctgggg tggaggtagc accactgcag 3300 agcttcatgc tgcggggtgg tgttgtagat gatccagtcg tagcaggagc gctgggcgtg 3360 gtgcctaaaa atgtctttca gtagcaagct gattgccagg ggcaggccct tggtgtaagt 3420 gtttacaaag cggttaagct gggatgggtg catacgtggg gatatgagat gcatcttgga 3480 ctgtattttt aggttggcta tgttcccagc catatccctc cggggattca tgttgtgcag 3540 aaccaccagc acagtgtatc cggtgcactt gggaaatttg tcatgtagct tagaaggaaa 3600 tgcgtggaag aacttggaga cgcccttgtg acctccaaga ttttccatgc attcgtccat 3660 aatgatggca atgggcccac gggcggcggc ctgggcgaag atatttctgg gatcactaac 3720 gtcatagttg tgttccagga tgagatcgtc ataggccatt tttacaaagc gcgggcggag 3780 ggtgccagac tgcggtataa tggttccatc cggcccaggg gcgtagttac cctcacagat 3840 ttgcatttcc cacgctttga gttcagatgg ggggatcatg tctacctgcg gggcgatgaa 3900 gaaaacggtt tccggggtag gggagatcag ctgggaagaa agcaggttcc tgagcagctg 3960 cgacttaccg cagccggtgg gcccgtaaat cacacctatt accgggtgca actggtagtt 4020 aagagagctg cagctgccgt catccctgag caggggggcc acttcgttaa gcatgtccct 4080 gactcgcatg ttttccctga ccaaatccgc cagaaggcgc tcgccgccca gcgatagcag 4140 ttcttgcaag gaagcaaagt ttttcaacgg tttgagaccg tccgccgtag gcatgctttt 4200 gagcgtttga ccaagcagtt ccaggcggtc ccacagctcg gtcacctgct ctacggcatc 4260 tcgatccagc atatctcctc gtttcgcggg ttggggcggc tttcgctgta cggcagtagt 4320 cggtgctcgt ccagacgggc cagggtcatg tctttccacg ggcgcagggt cctcgtcagc 4380 gtagtctggg tcacggtgaa ggggtgcgct ccgggctgcg cgctggccag ggtgcgcttg 4440 aggctggtcc tgctggtgct gaagcgctgc cggtcttcgc cctgcgcgtc ggccaggtag 4500 catttgacca tggtgtcata gtccagcccc tccgcggcgt ggcccttggc gcgcagcttg 4560 cccttggagg aggcgccgca cgaggggcag tgcagacttt tgagggcgta gagcttgggc 4620 gcgagaaata ccgattccgg ggagtaggca tccgcgccgc aggccccgca gacggtctcg 4680 cattccacga gccaggtgag ctctggccgt tcggggtcaa aaaccaggtt tcccccatgc 4740 tttttgatgc gtttcttacc tctggtttcc atgagccggt gtccacgctc ggtgacgaaa 4800 aggctgtccg tgtccccgta tacagacttg agagggagtt taaacgaatt caatagcttg 4860 ttgcatgggc ggcgatataa aatgcaaggt gctgctcaaa aaatcaggca aagcctcgcg 4920 caaaaaagaa agcacatcgt agtcatgctc atgcagataa aggcaggtaa gctccggaac 4980 caccacagaa aaagacacca tttttctctc aaacatgtct gcgggtttct gcataaacac 5040 aaaataaaat aacaaaaaaa catttaaaca ttagaagcct gtcttacaac aggaaaaaca 5100 acccttataa gcataagacg gactacggcc atgccggcgt gaccgtaaaa aaactggtca 5160 ccgtgattaa aaagcaccac cgacagctcc tcggtcatgt ccggagtcat aatgtaagac 5220 tcggtaaaca catcaggttg attcatcggt cagtgctaaa aagcgaccga aatagcccgg 5280 gggaatacat acccgcaggc gtagagacaa cattacagcc cccataggag gtataacaaa 5340 attaatagga gagaaaaaca cataaacacc tgaaaaaccc tcctgcctag gcaaaatagc 5400 accctcccgc tccagaacaa catacagcgc ttcacagcgg cagcctaaca gtcagcctta 5460 ccagtaaaaa agaaaaccta ttaaaaaaac accactcgac acggcaccag ctcaatcagt 5520 cacagtgtaa aaaagggcca agtgcagagc gagtatatat aggactaaaa aatgacgtaa 5580 cggttaaagt ccacaaaaaa cacccagaaa accgcacgcg aacctacgcc cagaaacgaa 5640 agccaaaaaa cccacaactt cctcaaatcg tcacttccgt tttcccacgt tacgtaactt 5700 cccattttaa gaaaactaca attcccaaca catacaagtt actccgccct aaaacctacg 5760 tcacccgccc cgttcccacg ccccgcgcca cgtcacaaac tccaccccct cattatcata 5820 ttggcttcaa tccaaaataa ggtatattat tgatgatgtt aattaacatg catggatcca 5880 tatgcggtgt gaaataccgc acagatgcgt aaggagaaaa taccgcatca ggcgctcttc 5940 cgcttcctcg ctcactgact cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc 6000 tcactcaaag gcggtaatac ggttatccac agaatcaggg gataacgcag gaaagaacat 6060 gtgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt 6120 ccataggctc cgcccccctg acgagcatca caaaaatcga cgctcaagtc agaggtggcg 6180 aaacccgaca ggactataaa gataccaggc gtttccccct ggaagctccc tcgtgcgctc 6240 tcctgttccg accctgccgc ttaccggata cctgtccgcc tttctccctt cgggaagcgt 6300 ggcgctttct catagctcac gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa 6360 gctgggctgt gtgcacgaac cccccgttca gcccgaccgc tgcgccttat ccggtaacta 6420 tcgtcttgag tccaacccgg taagacacga cttatcgcca ctggcagcag ccactggtaa 6480 caggattagc agagcgaggt atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa 6540 ctacggctac actagaagga cagtatttgg tatctgcgct ctgctgaagc cagttacctt 6600 cggaaaaaga gttggtagct cttgatccgg caaacaaacc accgctggta gcggtggttt 6660 ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga tctcaagaag atcctttgat 6720 cttttctacg gggtctgacg ctcagtggaa cgaaaactca cgttaaggga ttttggtcat 6780 gagattatca aaaaggatct tcacctagat ccttttaaat taaaaatgaa gttttaaatc 6840 aatctaaagt atatatgagt aaacttggtc tgacagttac caatgcttaa tcagtgaggc 6900 acctatctca gcgatctgtc tatttcgttc atccatagtt gcctgactcc ccgtcgtgta 6960 gataactacg atacgggagg gcttaccatc tggccccagt gctgcaatga taccgcgaga 7020 cccacgctca ccggctccag atttatcagc aataaaccag ccagccggaa gggccgagcg 7080 cagaagtggt cctgcaactt tatccgcctc catccagtct attaattgtt gccgggaagc 7140 tagagtaagt agttcgccag ttaatagttt gcgcaacgtt gttgccattg ctgcagccat 7200 gagattatca aaaaggatct tcacctagat ccttttcacg tagaaagcca gtccgcagaa 7260 acggtgctga ccccggatga atgtcagcta ctgggctatc tggacaaggg aaaacgcaag 7320 cgcaaagaga aagcaggtag cttgcagtgg gcttacatgg cgatagctag actgggcggt 7380 tttatggaca gcaagcgaac cggaattgcc agctggggcg ccctctggta aggttgggaa 7440 gccctgcaaa gtaaactgga tggctttctc gccgccaagg atctgatggc gcaggggatc 7500 aagctctgat caagagacag gatgaggatc gtttcgcatg attgaacaag atggattgca 7560 cgcaggttct ccggccgctt gggtggagag gctattcggc tatgactggg cacaacagac 7620 aatcggctgc tctgatgccg ccgtgttccg gctgtcagcg caggggcgcc cggttctttt 7680 tgtcaagacc gacctgtccg gtgccctgaa tgaactgcaa gacgaggcag cgcggctatc 7740 gtggctggcc acgacgggcg ttccttgcgc agctgtgctc gacgttgtca ctgaagcggg 7800 aagggactgg ctgctattgg gcgaagtgcc ggggcaggat ctcctgtcat ctcaccttgc 7860 tcctgccgag aaagtatcca tcatggctga tgcaatgcgg cggctgcata cgcttgatcc 7920 ggctacctgc ccattcgacc accaagcgaa acatcgcatc gagcgagcac gtactcggat 7980 ggaagccggt cttgtcgatc aggatgatct ggacgaagag catcaggggc tcgcgccagc 8040 cgaactgttc gccaggctca aggcgagcat gcccgacggc gaggatctcg tcgtgaccca 8100 tggcgatgcc tgcttgccga atatcatggt ggaaaatggc cgcttttctg gattcatcga 8160 ctgtggccgg ctgggtgtgg cggaccgcta tcaggacata gcgttggcta cccgtgatat 8220 tgctgaagag cttggcggcg aatgggctga ccgcttcctc gtgctttacg gtatcgccgc 8280 tcccgattcg cagcgcatcg ccttctatcg ccttcttgac gagttcttct gaattttgtt 8340 aaaatttttg ttaaatcagc tcatttttta accaataggc cgaaatcggc aacatccctt 8400 ataaatcaaa agaatagacc gcgatagggt tgagtgttgt tccagtttgg aacaagagtc 8460 cactattaaa gaacgtggac tccaacgtca aagggcgaaa aaccgtctat cagggcgatg 8520 gcccactacg tgaaccatca cccaaatcaa gttttttgcg gtcgaggtgc cgtaaagctc 8580 taaatcggaa ccctaaaggg agcccccgat ttagagcttg acggggaaag ccggcgaacg 8640 tggcgagaaa ggaagggaag aaagcgaaag gagcgggcgc tagggcgctg gcaagtgtag 8700 cggtcacgct gcgcgtaacc accacacccg cgcgcttaat gcgccgctac agggcgcgtc 8760 cattcgccat tcaggatcga attaattctt aat 8793 <210> 38 <211> 9939 <212> DNA <213> Artificial Sequence <220> <223> pAVQ-AS300KRib1-TK <400> 38 taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60 agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120 tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180 ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240 tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatcccta ctaggaccat aggtacatct tcagagtcct taactctttt 1680 aatttgttct ctataatggt gaatatcttc aaatgattta gtattattta tggcaaatac 1740 acaaagaaag ccctccccag tcctcatgta ctggtccctc attgcactgt actcctcttg 1800 acctgctgtg tcgagaatat ccaagagaca ggtttctcca tcaattacta cttgcttcct 1860 gtaggaatcc tctattgttg gatcatattc gtccacaaaa tgattctgaa ttagctgtat 1920 cgtcaaggca ctcttgcaag cttcattatc agcagctaaa agttatcagg catgcacctg 1980 gtagctagtc tttaaaccaa tagattgcat cggtttaaaa ggcaagaccg tcaaattgcg 2040 ggaaaggggt caacagccgt tcagtaccaa gtctcagggg aaactttgag atggccttgc 2100 aaagggtatg gtaataagct gacggacatg gtcctaacca cgcagccaag tcctaagtca 2160 acagatcttc tgttgatatg gatgcagttc acagactaaa tgtcggtcgg ggaagatgta 2220 ttcttctcat aagatatagt cggacctctc cttaatggga gctagcggat gaagtgatgc 2280 aacactggag ccgctgggaa ctaatttgta tgcgaaagta tattgattag ttttggagta 2340 ctcgcgatga tcacgcttcg tacccctgcc atcaacacgc gtctgcgttc gaccaggctg 2400 cgcgttctcg cggccatagc aaccgacgta cggcgttgcg ccctcgccgg cagcaagaag 2460 ccacggaagt ccgcctggag cagaaaatgc ccacgctact gcgggtttat atagacggtc 2520 ctcacgggat ggggaaaacc accaccacgc aactgctggt ggccctgggt tcgcgcgacg 2580 atatcgtcta cgtacccgag ccgatgactt actggcaggt gctgggggct tccgagacaa 2640 tcgcgaacat ctacaccaca caacaccgcc tcgaccaggg tgagatatcg gccggggacg 2700 cggcggtggt aatgacaagc gcccagataa caatgggcat gccttatgcc gtgaccgacg 2760 ccgttctggc tcctcatgtc gggggggagg ctgggagttc acatgccccg cccccggccc 2820 tcaccctcat cttcgaccgc catcccatcg ccgccctcct gtgctacccg gccgcgcgat 2880 accttatggg cagcatgacc ccccaggccg tgctggcgtt cgtggccctc atcccgccga 2940 ccttgcccgg cacaaacatc gtgttggggg cccttccgga ggacagacac atcgaccgcc 3000 tggccaaacg ccagcgcccc ggcgagcggc ttgacctggc tatgctggcc gcgattcgcc 3060 gcgtttacgg gctgcttgcc aatacggtgc ggtatctgca gggcggcggg tcgtggtggg 3120 aggattgggg acagctttcg gggacggccg tgccgcccca gggtgccgag ccccagagca 3180 acgcgggccc acgaccccat atcggggaca cgttatttac cctgtttcgg gcccccgagt 3240 tgctggcccc caacggcgac ctgtataacg tgtttgcctg ggccttggac gtcttggcca 3300 aacgcctccg tcccatgcac gtctttatcc tggattacga ccaatcgccc gccggctgcc 3360 gggacgccct gctgcaactt acctccggga tggtccagac ccacgtcacc accccaggct 3420 ccataccgac gatctgcgac ctggcgcgca cgtttgcccg ggagatgggg gaggctaact 3480 gaagcttttc gaaagatccc aacgaaaaga gagaccacat ggtccttctt gagtttgtaa 3540 cagctgctgg gattacacat ggcatggatg aactgtacaa ctgaggatcc cccgacctcg 3600 acctctggct aataaaggaa atttattttc attgcaatag tgtgttggaa ttttttgtgt 3660 ctctcactcg gaaggacata tgggagggca aatcatttgg tcgagatccc tcggagatcg 3720 gatctgggcg tggttaaggg tgggaaagaa tatataaggt gggggtctta tgtagttttg 3780 tatctgtttt gcagcagccg ccgccgccat gagcaccaac tcgtttgatg gaagcattgt 3840 gagctcatat ttgacaacgc gcatgccccc atgggccggg gtgcgtcaga atgtgatggg 3900 ctccagcatt gatggtcgcc ccgtcctgcc cgcaaactct actaccttga cctacgagac 3960 cgtgtctgga acgccgttgg agactgcagc ctccgccgcc gcttcagccg ctgcagccac 4020 cgcccgcggg attgtgactg actttgcttt cctgagcccg cttgcaagca gtgcagcttc 4080 ccgttcatcc gcccgcgatg acaagttgac ggctcttttg gcacaattgg attctttgac 4140 ccgggaactt aatgtcgttt ctcagcagct gttggatctg cgccagcagg tttctgccct 4200 gaaggcttcc tcccctccca atgcggttta aaacataaat aaaaaaccag actctgtttg 4260 gatttggatc aagcaagtgt cttgctgtct ttatttaggg gttttgcgcg cgcggtaggc 4320 ccgggaccag cggtctcggt cgttgagggt cctgtgtatt ttttccagga cgtggtaaag 4380 gtgactctgg atgttcagat acatgggcat aagcccgtct ctggggtgga ggtagcacca 4440 ctgcagagct tcatgctgcg gggtggtgtt gtagatgatc cagtcgtagc aggagcgctg 4500 ggcgtggtgc ctaaaaatgt ctttcagtag caagctgatt gccaggggca ggcccttggt 4560 gtaagtgttt acaaagcggt taagctggga tgggtgcata cgtggggata tgagatgcat 4620 cttggactgt atttttaggt tggctatgtt cccagccata tccctccggg gattcatgtt 4680 gtgcagaacc accagcacag tgtatccggt gcacttggga aatttgtcat gtagcttaga 4740 aggaaatgcg tggaagaact tggagacgcc cttgtgacct ccaagatttt ccatgcattc 4800 gtccataatg atggcaatgg gcccacgggc ggcggcctgg gcgaagatat ttctgggatc 4860 actaacgtca tagttgtgtt ccaggatgag atcgtcatag gccattttta caaagcgcgg 4920 gcggagggtg ccagactgcg gtataatggt tccatccggc ccaggggcgt agttaccctc 4980 acagatttgc atttcccacg ctttgagttc agatgggggg atcatgtcta cctgcggggc 5040 gatgaagaaa acggtttccg gggtagggga gatcagctgg gaagaaagca ggttcctgag 5100 cagctgcgac ttaccgcagc cggtgggccc gtaaatcaca cctattaccg ggtgcaactg 5160 gtagttaaga gagctgcagc tgccgtcatc cctgagcagg ggggccactt cgttaagcat 5220 gtccctgact cgcatgtttt ccctgaccaa atccgccaga aggcgctcgc cgcccagcga 5280 tagcagttct tgcaaggaag caaagttttt caacggtttg agaccgtccg ccgtaggcat 5340 gcttttgagc gtttgaccaa gcagttccag gcggtcccac agctcggtca cctgctctac 5400 ggcatctcga tccagcatat ctcctcgttt cgcgggttgg ggcggctttc gctgtacggc 5460 agtagtcggt gctcgtccag acgggccagg gtcatgtctt tccacgggcg cagggtcctc 5520 gtcagcgtag tctgggtcac ggtgaagggg tgcgctccgg gctgcgcgct ggccagggtg 5580 cgcttgaggc tggtcctgct ggtgctgaag cgctgccggt cttcgccctg cgcgtcggcc 5640 aggtagcatt tgaccatggt gtcatagtcc agcccctccg cggcgtggcc cttggcgcgc 5700 agcttgccct tggaggaggc gccgcacgag gggcagtgca gacttttgag ggcgtagagc 5760 ttgggcgcga gaaataccga ttccggggag taggcatccg cgccgcaggc cccgcagacg 5820 gtctcgcatt ccacgagcca ggtgagctct ggccgttcgg ggtcaaaaac caggtttccc 5880 ccatgctttt tgatgcgttt cttacctctg gtttccatga gccggtgtcc acgctcggtg 5940 acgaaaaggc tgtccgtgtc cccgtataca gacttgagag ggagtttaaa cgaattcaat 6000 agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat caggcaaagc 6060 ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc aggtaagctc 6120 cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg gtttctgcat 6180 aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct tacaacagga 6240 aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc gtaaaaaaac 6300 tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg agtcataatg 6360 taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc gaccgaaata 6420 gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca taggaggtat 6480 aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct gcctaggcaa 6540 aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc ctaacagtca 6600 gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg caccagctca 6660 atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga ctaaaaaatg 6720 acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc tacgcccaga 6780 aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc ccacgttacg 6840 taacttccca ttttaagaaa actacaattc ccaacacata caagttactc cgccctaaaa 6900 cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca ccccctcatt 6960 atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt aacatgcatg 7020 gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc gcatcaggcg 7080 ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc ggcgagcggt 7140 atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata acgcaggaaa 7200 gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg cgttgctggc 7260 gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct caagtcagag 7320 gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa gctccctcgt 7380 gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc tcccttcggg 7440 aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt aggtcgttcg 7500 ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg ccttatccgg 7560 taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg cagcagccac 7620 tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct tgaagtggtg 7680 gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc tgaagccagt 7740 taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg ctggtagcgg 7800 tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc aagaagatcc 7860 tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt aagggatttt 7920 ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa aatgaagttt 7980 taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat gcttaatcag 8040 tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct gactccccgt 8100 cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg caatgatacc 8160 gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag ccggaagggc 8220 cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta attgttgccg 8280 ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg ccattgctgc 8340 agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga aagccagtcc 8400 gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga caagggaaaa 8460 cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat agctagactg 8520 ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct ctggtaaggt 8580 tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct gatggcgcag 8640 gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg aacaagatgg 8700 attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg actgggcaca 8760 acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg ggcgcccggt 8820 tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg aggcagcgcg 8880 gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg ttgtcactga 8940 agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc tgtcatctca 9000 ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc tgcatacgct 9060 tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc gagcacgtac 9120 tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc aggggctcgc 9180 gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg atctcgtcgt 9240 gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct tttctggatt 9300 catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt tggctacccg 9360 tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc tttacggtat 9420 cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt tcttctgaat 9480 tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa atcggcaaca 9540 tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca gtttggaaca 9600 agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc gtctatcagg 9660 gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg aggtgccgta 9720 aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg ggaaagccgg 9780 cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg gcgctggcaa 9840 gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc cgctacaggg 9900 cgcgtccatt cgccattcag gatcgaatta attcttaat 9939 <210> 39 <211> 8607 <212> DNA <213> Artificial Sequence <220> <223> pAVQ-AS100KRib2 <400> 39 taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60 agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120 tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180 ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240 tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatcccca tcaattacta cttgcttcct gtaggaatcc tctattgttg 1680 gatcatattc gtccacaaaa tgattctgaa ttagctgtat cgtcaaggca ctcttgcaag 1740 cttcatcatg gccgacagca aaagttatca ggcatgcacc tggtagctag tctttaaacc 1800 aatagattgc atcggtttaa aaggcaagac cgtcaaattg cgggaaaggg gtcaacagcc 1860 gttcagtacc aagtctcagg ggaaactttg agatggcctt gcaaagggta tggtaataag 1920 ctgacggaca tggtcctaac cacgcagcca agtcctaagt caacagatct tctgttgata 1980 tggatgcagt tcacagacta aatgtcggtc ggggaagatg tattcttctc ataagatata 2040 gtcggacctc tccttaatgg gagctagcgg atgaagtgat gcaacactgg agccgctggg 2100 aactaatttg tatgcgaaag tatattgatt agttttggag tactcgcgac atgatcacga 2160 aagatcccaa cgaaaagaga gaccacatgg tccttcttga gtttgtaaca gctgctggga 2220 ttacacatgg catggatgaa ctgtacaact gaggatcccc cgacctcgac ctctggctaa 2280 taaaggaaat ttattttcat tgcaatagtg tgttggaatt ttttgtgtct ctcactcgga 2340 aggacatatg ggagggcaaa tcatttggtc gagatccctc ggagatcgga tctgggcgtg 2400 gttaagggtg ggaaagaata tataaggtgg gggtcttatg tagttttgta tctgttttgc 2460 agcagccgcc gccgccatga gcaccaactc gtttgatgga agcattgtga gctcatattt 2520 gacaacgcgc atgcccccat gggccggggt gcgtcagaat gtgatgggct ccagcattga 2580 tggtcgcccc gtcctgcccg caaactctac taccttgacc tacgagaccg tgtctggaac 2640 gccgttggag actgcagcct ccgccgccgc ttcagccgct gcagccaccg cccgcgggat 2700 tgtgactgac tttgctttcc tgagcccgct tgcaagcagt gcagcttccc gttcatccgc 2760 ccgcgatgac aagttgacgg ctcttttggc acaattggat tctttgaccc gggaacttaa 2820 tgtcgtttct cagcagctgt tggatctgcg ccagcaggtt tctgccctga aggcttcctc 2880 ccctcccaat gcggtttaaa acataaataa aaaaccagac tctgtttgga tttggatcaa 2940 gcaagtgtct tgctgtcttt atttaggggt tttgcgcgcg cggtaggccc gggaccagcg 3000 gtctcggtcg ttgagggtcc tgtgtatttt ttccaggacg tggtaaaggt gactctggat 3060 gttcagatac atgggcataa gcccgtctct ggggtggagg tagcaccact gcagagcttc 3120 atgctgcggg gtggtgttgt agatgatcca gtcgtagcag gagcgctggg cgtggtgcct 3180 aaaaatgtct ttcagtagca agctgattgc caggggcagg cccttggtgt aagtgtttac 3240 aaagcggtta agctgggatg ggtgcatacg tggggatatg agatgcatct tggactgtat 3300 ttttaggttg gctatgttcc cagccatatc cctccgggga ttcatgttgt gcagaaccac 3360 cagcacagtg tatccggtgc acttgggaaa tttgtcatgt agcttagaag gaaatgcgtg 3420 gaagaacttg gagacgccct tgtgacctcc aagattttcc atgcattcgt ccataatgat 3480 ggcaatgggc ccacgggcgg cggcctgggc gaagatattt ctgggatcac taacgtcata 3540 gttgtgttcc aggatgagat cgtcataggc catttttaca aagcgcgggc ggagggtgcc 3600 agactgcggt ataatggttc catccggccc aggggcgtag ttaccctcac agatttgcat 3660 ttcccacgct ttgagttcag atggggggat catgtctacc tgcggggcga tgaagaaaac 3720 ggtttccggg gtaggggaga tcagctggga agaaagcagg ttcctgagca gctgcgactt 3780 accgcagccg gtgggcccgt aaatcacacc tattaccggg tgcaactggt agttaagaga 3840 gctgcagctg ccgtcatccc tgagcagggg ggccacttcg ttaagcatgt ccctgactcg 3900 catgttttcc ctgaccaaat ccgccagaag gcgctcgccg cccagcgata gcagttcttg 3960 caaggaagca aagtttttca acggtttgag accgtccgcc gtaggcatgc ttttgagcgt 4020 ttgaccaagc agttccaggc ggtcccacag ctcggtcacc tgctctacgg catctcgatc 4080 cagcatatct cctcgtttcg cgggttgggg cggctttcgc tgtacggcag tagtcggtgc 4140 tcgtccagac gggccagggt catgtctttc cacgggcgca gggtcctcgt cagcgtagtc 4200 tgggtcacgg tgaaggggtg cgctccgggc tgcgcgctgg ccagggtgcg cttgaggctg 4260 gtcctgctgg tgctgaagcg ctgccggtct tcgccctgcg cgtcggccag gtagcatttg 4320 accatggtgt catagtccag cccctccgcg gcgtggccct tggcgcgcag cttgcccttg 4380 gaggaggcgc cgcacgaggg gcagtgcaga cttttgaggg cgtagagctt gggcgcgaga 4440 aataccgatt ccggggagta ggcatccgcg ccgcaggccc cgcagacggt ctcgcattcc 4500 acgagccagg tgagctctgg ccgttcgggg tcaaaaacca ggtttccccc atgctttttg 4560 atgcgtttct tacctctggt ttccatgagc cggtgtccac gctcggtgac gaaaaggctg 4620 tccgtgtccc cgtatacaga cttgagaggg agtttaaacg aattcaatag cttgttgcat 4680 gggcggcgat ataaaatgca aggtgctgct caaaaaatca ggcaaagcct cgcgcaaaaa 4740 agaaagcaca tcgtagtcat gctcatgcag ataaaggcag gtaagctccg gaaccaccac 4800 agaaaaagac accatttttc tctcaaacat gtctgcgggt ttctgcataa acacaaaata 4860 aaataacaaa aaaacattta aacattagaa gcctgtctta caacaggaaa aacaaccctt 4920 ataagcataa gacggactac ggccatgccg gcgtgaccgt aaaaaaactg gtcaccgtga 4980 ttaaaaagca ccaccgacag ctcctcggtc atgtccggag tcataatgta agactcggta 5040 aacacatcag gttgattcat cggtcagtgc taaaaagcga ccgaaatagc ccgggggaat 5100 acatacccgc aggcgtagag acaacattac agcccccata ggaggtataa caaaattaat 5160 aggagagaaa aacacataaa cacctgaaaa accctcctgc ctaggcaaaa tagcaccctc 5220 ccgctccaga acaacataca gcgcttcaca gcggcagcct aacagtcagc cttaccagta 5280 aaaaagaaaa cctattaaaa aaacaccact cgacacggca ccagctcaat cagtcacagt 5340 gtaaaaaagg gccaagtgca gagcgagtat atataggact aaaaaatgac gtaacggtta 5400 aagtccacaa aaaacaccca gaaaaccgca cgcgaaccta cgcccagaaa cgaaagccaa 5460 aaaacccaca acttcctcaa atcgtcactt ccgttttccc acgttacgta acttcccatt 5520 ttaagaaaac tacaattccc aacacataca agttactccg ccctaaaacc tacgtcaccc 5580 gccccgttcc cacgccccgc gccacgtcac aaactccacc ccctcattat catattggct 5640 tcaatccaaa ataaggtata ttattgatga tgttaattaa catgcatgga tccatatgcg 5700 gtgtgaaata ccgcacagat gcgtaaggag aaaataccgc atcaggcgct cttccgcttc 5760 ctcgctcact gactcgctgc gctcggtcgt tcggctgcgg cgagcggtat cagctcactc 5820 aaaggcggta atacggttat ccacagaatc aggggataac gcaggaaaga acatgtgagc 5880 aaaaggccag caaaaggcca ggaaccgtaa aaaggccgcg ttgctggcgt ttttccatag 5940 gctccgcccc cctgacgagc atcacaaaaa tcgacgctca agtcagaggt ggcgaaaccc 6000 gacaggacta taaagatacc aggcgtttcc ccctggaagc tccctcgtgc gctctcctgt 6060 tccgaccctg ccgcttaccg gatacctgtc cgcctttctc ccttcgggaa gcgtggcgct 6120 ttctcatagc tcacgctgta ggtatctcag ttcggtgtag gtcgttcgct ccaagctggg 6180 ctgtgtgcac gaaccccccg ttcagcccga ccgctgcgcc ttatccggta actatcgtct 6240 tgagtccaac ccggtaagac acgacttatc gccactggca gcagccactg gtaacaggat 6300 tagcagagcg aggtatgtag gcggtgctac agagttcttg aagtggtggc ctaactacgg 6360 ctacactaga aggacagtat ttggtatctg cgctctgctg aagccagtta ccttcggaaa 6420 aagagttggt agctcttgat ccggcaaaca aaccaccgct ggtagcggtg gtttttttgt 6480 ttgcaagcag cagattacgc gcagaaaaaa aggatctcaa gaagatcctt tgatcttttc 6540 tacggggtct gacgctcagt ggaacgaaaa ctcacgttaa gggattttgg tcatgagatt 6600 atcaaaaagg atcttcacct agatcctttt aaattaaaaa tgaagtttta aatcaatcta 6660 aagtatatat gagtaaactt ggtctgacag ttaccaatgc ttaatcagtg aggcacctat 6720 ctcagcgatc tgtctatttc gttcatccat agttgcctga ctccccgtcg tgtagataac 6780 tacgatacgg gagggcttac catctggccc cagtgctgca atgataccgc gagacccacg 6840 ctcaccggct ccagatttat cagcaataaa ccagccagcc ggaagggccg agcgcagaag 6900 tggtcctgca actttatccg cctccatcca gtctattaat tgttgccggg aagctagagt 6960 aagtagttcg ccagttaata gtttgcgcaa cgttgttgcc attgctgcag ccatgagatt 7020 atcaaaaagg atcttcacct agatcctttt cacgtagaaa gccagtccgc agaaacggtg 7080 ctgaccccgg atgaatgtca gctactgggc tatctggaca agggaaaacg caagcgcaaa 7140 gagaaagcag gtagcttgca gtgggcttac atggcgatag ctagactggg cggttttatg 7200 gacagcaagc gaaccggaat tgccagctgg ggcgccctct ggtaaggttg ggaagccctg 7260 caaagtaaac tggatggctt tctcgccgcc aaggatctga tggcgcaggg gatcaagctc 7320 tgatcaagag acaggatgag gatcgtttcg catgattgaa caagatggat tgcacgcagg 7380 ttctccggcc gcttgggtgg agaggctatt cggctatgac tgggcacaac agacaatcgg 7440 ctgctctgat gccgccgtgt tccggctgtc agcgcagggg cgcccggttc tttttgtcaa 7500 gaccgacctg tccggtgccc tgaatgaact gcaagacgag gcagcgcggc tatcgtggct 7560 ggccacgacg ggcgttcctt gcgcagctgt gctcgacgtt gtcactgaag cgggaaggga 7620 ctggctgcta ttgggcgaag tgccggggca ggatctcctg tcatctcacc ttgctcctgc 7680 cgagaaagta tccatcatgg ctgatgcaat gcggcggctg catacgcttg atccggctac 7740 ctgcccattc gaccaccaag cgaaacatcg catcgagcga gcacgtactc ggatggaagc 7800 cggtcttgtc gatcaggatg atctggacga agagcatcag gggctcgcgc cagccgaact 7860 gttcgccagg ctcaaggcga gcatgcccga cggcgaggat ctcgtcgtga cccatggcga 7920 tgcctgcttg ccgaatatca tggtggaaaa tggccgcttt tctggattca tcgactgtgg 7980 ccggctgggt gtggcggacc gctatcagga catagcgttg gctacccgtg atattgctga 8040 agagcttggc ggcgaatggg ctgaccgctt cctcgtgctt tacggtatcg ccgctcccga 8100 ttcgcagcgc atcgccttct atcgccttct tgacgagttc ttctgaattt tgttaaaatt 8160 tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaacatc ccttataaat 8220 caaaagaata gaccgcgata gggttgagtg ttgttccagt ttggaacaag agtccactat 8280 taaagaacgt ggactccaac gtcaaagggc gaaaaaccgt ctatcagggc gatggcccac 8340 tacgtgaacc atcacccaaa tcaagttttt tgcggtcgag gtgccgtaaa gctctaaatc 8400 ggaaccctaa agggagcccc cgatttagag cttgacgggg aaagccggcg aacgtggcga 8460 gaaaggaagg gaagaaagcg aaaggagcgg gcgctagggc gctggcaagt gtagcggtca 8520 cgctgcgcgt aaccaccaca cccgcgcgct taatgcgccg ctacagggcg cgtccattcg 8580 ccattcagga tcgaattaat tcttaat 8607 <210> 40 <211> 9737 <212> DNA <213> Artificial Sequence <220> <223> pAVQ-AS100KRib2-TK <400> 40 taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60 agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120 tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180 ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240 tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatcccca tcaattacta cttgcttcct gtaggaatcc tctattgttg 1680 gatcatattc gtccacaaaa tgattctgaa ttagctgtat cgtcaaggca ctcttgcaag 1740 cttcatcatg gccgacagca aaagttatca ggcatgcacc tggtagctag tctttaaacc 1800 aatagattgc atcggtttaa aaggcaagac cgtcaaattg cgggaaaggg gtcaacagcc 1860 gttcagtacc aagtctcagg ggaaactttg agatggcctt gcaaagggta tggtaataag 1920 ctgacggaca tggtcctaac cacgcagcca agtcctaagt caacagatct tctgttgata 1980 tggatgcagt tcacagacta aatgtcggtc ggggaagatg tattcttctc ataagatata 2040 gtcggacctc tccttaatgg gagctagcgg atgaagtgat gcaacactgg agccgctggg 2100 aactaatttg tatgcgaaag tatattgatt agttttggag tactcgcgac atgatcacgc 2160 ttcgtacccc tgccatcaac acgcgtctgc gttcgaccag gctgcgcgtt ctcgcggcca 2220 tagcaaccga cgtacggcgt tgcgccctcg ccggcagcaa gaagccacgg aagtccgcct 2280 ggagcagaaa atgcccacgc tactgcgggt ttatatagac ggtcctcacg ggatggggaa 2340 aaccaccacc acgcaactgc tggtggccct gggttcgcgc gacgatatcg tctacgtacc 2400 cgagccgatg acttactggc aggtgctggg ggcttccgag acaatcgcga acatctacac 2460 cacacaacac cgcctcgacc agggtgagat atcggccggg gacgcggcgg tggtaatgac 2520 aagcgcccag ataacaatgg gcatgcctta tgccgtgacc gacgccgttc tggctcctca 2580 tgtcgggggg gaggctggga gttcacatgc cccgcccccg gccctcaccc tcatcttcga 2640 ccgccatccc atcgccgccc tcctgtgcta cccggccgcg cgatacctta tgggcagcat 2700 gaccccccag gccgtgctgg cgttcgtggc cctcatcccg ccgaccttgc ccggcacaaa 2760 catcgtgttg ggggcccttc cggaggacag acacatcgac cgcctggcca aacgccagcg 2820 ccccggcgag cggcttgacc tggctatgct ggccgcgatt cgccgcgttt acgggctgct 2880 tgccaatacg gtgcggtatc tgcagggcgg cgggtcgtgg tgggaggatt ggggacagct 2940 ttcggggacg gccgtgccgc cccagggtgc cgagccccag agcaacgcgg gcccacgacc 3000 ccatatcggg gacacgttat ttaccctgtt tcgggccccc gagttgctgg cccccaacgg 3060 cgacctgtat aacgtgtttg cctgggcctt ggacgtcttg gccaaacgcc tccgtcccat 3120 gcacgtcttt atcctggatt acgaccaatc gcccgccggc tgccgggacg ccctgctgca 3180 acttacctcc gggatggtcc agacccacgt caccacccca ggctccatac cgacgatctg 3240 cgacctggcg cgcacgtttg cccgggagat gggggaggct aataattcga aagatcccaa 3300 cgaaaagaga gaccacatgg tccttcttga gtttgtaaca gctgctggga ttacacatgg 3360 catggatgaa ctgtacaact gaggatcccc cgacctcgac ctctggctaa taaaggaaat 3420 ttattttcat tgcaatagtg tgttggaatt ttttgtgtct ctcactcgga aggacatatg 3480 ggagggcaaa tcatttggtc gagatccctc ggagatcgga tctgggcgtg gttaagggtg 3540 ggaaagaata tataaggtgg gggtcttatg tagttttgta tctgttttgc agcagccgcc 3600 gccgccatga gcaccaactc gtttgatgga agcattgtga gctcatattt gacaacgcgc 3660 atgcccccat gggccggggt gcgtcagaat gtgatgggct ccagcattga tggtcgcccc 3720 gtcctgcccg caaactctac taccttgacc tacgagaccg tgtctggaac gccgttggag 3780 actgcagcct ccgccgccgc ttcagccgct gcagccaccg cccgcgggat tgtgactgac 3840 tttgctttcc tgagcccgct tgcaagcagt gcagcttccc gttcatccgc ccgcgatgac 3900 aagttgacgg ctcttttggc acaattggat tctttgaccc gggaacttaa tgtcgtttct 3960 cagcagctgt tggatctgcg ccagcaggtt tctgccctga aggcttcctc ccctcccaat 4020 gcggtttaaa acataaataa aaaaccagac tctgtttgga tttggatcaa gcaagtgtct 4080 tgctgtcttt atttaggggt tttgcgcgcg cggtaggccc gggaccagcg gtctcggtcg 4140 ttgagggtcc tgtgtatttt ttccaggacg tggtaaaggt gactctggat gttcagatac 4200 atgggcataa gcccgtctct ggggtggagg tagcaccact gcagagcttc atgctgcggg 4260 gtggtgttgt agatgatcca gtcgtagcag gagcgctggg cgtggtgcct aaaaatgtct 4320 ttcagtagca agctgattgc caggggcagg cccttggtgt aagtgtttac aaagcggtta 4380 agctgggatg ggtgcatacg tggggatatg agatgcatct tggactgtat ttttaggttg 4440 gctatgttcc cagccatatc cctccgggga ttcatgttgt gcagaaccac cagcacagtg 4500 tatccggtgc acttgggaaa tttgtcatgt agcttagaag gaaatgcgtg gaagaacttg 4560 gagacgccct tgtgacctcc aagattttcc atgcattcgt ccataatgat ggcaatgggc 4620 ccacgggcgg cggcctgggc gaagatattt ctgggatcac taacgtcata gttgtgttcc 4680 aggatgagat cgtcataggc catttttaca aagcgcgggc ggagggtgcc agactgcggt 4740 ataatggttc catccggccc aggggcgtag ttaccctcac agatttgcat ttcccacgct 4800 ttgagttcag atggggggat catgtctacc tgcggggcga tgaagaaaac ggtttccggg 4860 gtaggggaga tcagctggga agaaagcagg ttcctgagca gctgcgactt accgcagccg 4920 gtgggcccgt aaatcacacc tattaccggg tgcaactggt agttaagaga gctgcagctg 4980 ccgtcatccc tgagcagggg ggccacttcg ttaagcatgt ccctgactcg catgttttcc 5040 ctgaccaaat ccgccagaag gcgctcgccg cccagcgata gcagttcttg caaggaagca 5100 aagtttttca acggtttgag accgtccgcc gtaggcatgc ttttgagcgt ttgaccaagc 5160 agttccaggc ggtcccacag ctcggtcacc tgctctacgg catctcgatc cagcatatct 5220 cctcgtttcg cgggttgggg cggctttcgc tgtacggcag tagtcggtgc tcgtccagac 5280 gggccagggt catgtctttc cacgggcgca gggtcctcgt cagcgtagtc tgggtcacgg 5340 tgaaggggtg cgctccgggc tgcgcgctgg ccagggtgcg cttgaggctg gtcctgctgg 5400 tgctgaagcg ctgccggtct tcgccctgcg cgtcggccag gtagcatttg accatggtgt 5460 catagtccag cccctccgcg gcgtggccct tggcgcgcag cttgcccttg gaggaggcgc 5520 cgcacgaggg gcagtgcaga cttttgaggg cgtagagctt gggcgcgaga aataccgatt 5580 ccggggagta ggcatccgcg ccgcaggccc cgcagacggt ctcgcattcc acgagccagg 5640 tgagctctgg ccgttcgggg tcaaaaacca ggtttccccc atgctttttg atgcgtttct 5700 tacctctggt ttccatgagc cggtgtccac gctcggtgac gaaaaggctg tccgtgtccc 5760 cgtatacaga cttgagaggg agtttaaacg aattcaatag cttgttgcat gggcggcgat 5820 ataaaatgca aggtgctgct caaaaaatca ggcaaagcct cgcgcaaaaa agaaagcaca 5880 tcgtagtcat gctcatgcag ataaaggcag gtaagctccg gaaccaccac agaaaaagac 5940 accatttttc tctcaaacat gtctgcgggt ttctgcataa acacaaaata aaataacaaa 6000 aaaacattta aacattagaa gcctgtctta caacaggaaa aacaaccctt ataagcataa 6060 gacggactac ggccatgccg gcgtgaccgt aaaaaaactg gtcaccgtga ttaaaaagca 6120 ccaccgacag ctcctcggtc atgtccggag tcataatgta agactcggta aacacatcag 6180 gttgattcat cggtcagtgc taaaaagcga ccgaaatagc ccgggggaat acatacccgc 6240 aggcgtagag acaacattac agcccccata ggaggtataa caaaattaat aggagagaaa 6300 aacacataaa cacctgaaaa accctcctgc ctaggcaaaa tagcaccctc ccgctccaga 6360 acaacataca gcgcttcaca gcggcagcct aacagtcagc cttaccagta aaaaagaaaa 6420 cctattaaaa aaacaccact cgacacggca ccagctcaat cagtcacagt gtaaaaaagg 6480 gccaagtgca gagcgagtat atataggact aaaaaatgac gtaacggtta aagtccacaa 6540 aaaacaccca gaaaaccgca cgcgaaccta cgcccagaaa cgaaagccaa aaaacccaca 6600 acttcctcaa atcgtcactt ccgttttccc acgttacgta acttcccatt ttaagaaaac 6660 tacaattccc aacacataca agttactccg ccctaaaacc tacgtcaccc gccccgttcc 6720 cacgccccgc gccacgtcac aaactccacc ccctcattat catattggct tcaatccaaa 6780 ataaggtata ttattgatga tgttaattaa catgcatgga tccatatgcg gtgtgaaata 6840 ccgcacagat gcgtaaggag aaaataccgc atcaggcgct cttccgcttc ctcgctcact 6900 gactcgctgc gctcggtcgt tcggctgcgg cgagcggtat cagctcactc aaaggcggta 6960 atacggttat ccacagaatc aggggataac gcaggaaaga acatgtgagc aaaaggccag 7020 caaaaggcca ggaaccgtaa aaaggccgcg ttgctggcgt ttttccatag gctccgcccc 7080 cctgacgagc atcacaaaaa tcgacgctca agtcagaggt ggcgaaaccc gacaggacta 7140 taaagatacc aggcgtttcc ccctggaagc tccctcgtgc gctctcctgt tccgaccctg 7200 ccgcttaccg gatacctgtc cgcctttctc ccttcgggaa gcgtggcgct ttctcatagc 7260 tcacgctgta ggtatctcag ttcggtgtag gtcgttcgct ccaagctggg ctgtgtgcac 7320 gaaccccccg ttcagcccga ccgctgcgcc ttatccggta actatcgtct tgagtccaac 7380 ccggtaagac acgacttatc gccactggca gcagccactg gtaacaggat tagcagagcg 7440 aggtatgtag gcggtgctac agagttcttg aagtggtggc ctaactacgg ctacactaga 7500 aggacagtat ttggtatctg cgctctgctg aagccagtta ccttcggaaa aagagttggt 7560 agctcttgat ccggcaaaca aaccaccgct ggtagcggtg gtttttttgt ttgcaagcag 7620 cagattacgc gcagaaaaaa aggatctcaa gaagatcctt tgatcttttc tacggggtct 7680 gacgctcagt ggaacgaaaa ctcacgttaa gggattttgg tcatgagatt atcaaaaagg 7740 atcttcacct agatcctttt aaattaaaaa tgaagtttta aatcaatcta aagtatatat 7800 gagtaaactt ggtctgacag ttaccaatgc ttaatcagtg aggcacctat ctcagcgatc 7860 tgtctatttc gttcatccat agttgcctga ctccccgtcg tgtagataac tacgatacgg 7920 gagggcttac catctggccc cagtgctgca atgataccgc gagacccacg ctcaccggct 7980 ccagatttat cagcaataaa ccagccagcc ggaagggccg agcgcagaag tggtcctgca 8040 actttatccg cctccatcca gtctattaat tgttgccggg aagctagagt aagtagttcg 8100 ccagttaata gtttgcgcaa cgttgttgcc attgctgcag ccatgagatt atcaaaaagg 8160 atcttcacct agatcctttt cacgtagaaa gccagtccgc agaaacggtg ctgaccccgg 8220 atgaatgtca gctactgggc tatctggaca agggaaaacg caagcgcaaa gagaaagcag 8280 gtagcttgca gtgggcttac atggcgatag ctagactggg cggttttatg gacagcaagc 8340 gaaccggaat tgccagctgg ggcgccctct ggtaaggttg ggaagccctg caaagtaaac 8400 tggatggctt tctcgccgcc aaggatctga tggcgcaggg gatcaagctc tgatcaagag 8460 acaggatgag gatcgtttcg catgattgaa caagatggat tgcacgcagg ttctccggcc 8520 gcttgggtgg agaggctatt cggctatgac tgggcacaac agacaatcgg ctgctctgat 8580 gccgccgtgt tccggctgtc agcgcagggg cgcccggttc tttttgtcaa gaccgacctg 8640 tccggtgccc tgaatgaact gcaagacgag gcagcgcggc tatcgtggct ggccacgacg 8700 ggcgttcctt gcgcagctgt gctcgacgtt gtcactgaag cgggaaggga ctggctgcta 8760 ttgggcgaag tgccggggca ggatctcctg tcatctcacc ttgctcctgc cgagaaagta 8820 tccatcatgg ctgatgcaat gcggcggctg catacgcttg atccggctac ctgcccattc 8880 gaccaccaag cgaaacatcg catcgagcga gcacgtactc ggatggaagc cggtcttgtc 8940 gatcaggatg atctggacga agagcatcag gggctcgcgc cagccgaact gttcgccagg 9000 ctcaaggcga gcatgcccga cggcgaggat ctcgtcgtga cccatggcga tgcctgcttg 9060 ccgaatatca tggtggaaaa tggccgcttt tctggattca tcgactgtgg ccggctgggt 9120 gtggcggacc gctatcagga catagcgttg gctacccgtg atattgctga agagcttggc 9180 ggcgaatggg ctgaccgctt cctcgtgctt tacggtatcg ccgctcccga ttcgcagcgc 9240 atcgccttct atcgccttct tgacgagttc ttctgaattt tgttaaaatt tttgttaaat 9300 cagctcattt tttaaccaat aggccgaaat cggcaacatc ccttataaat caaaagaata 9360 gaccgcgata gggttgagtg ttgttccagt ttggaacaag agtccactat taaagaacgt 9420 ggactccaac gtcaaagggc gaaaaaccgt ctatcagggc gatggcccac tacgtgaacc 9480 atcacccaaa tcaagttttt tgcggtcgag gtgccgtaaa gctctaaatc ggaaccctaa 9540 agggagcccc cgatttagag cttgacgggg aaagccggcg aacgtggcga gaaaggaagg 9600 gaagaaagcg aaaggagcgg gcgctagggc gctggcaagt gtagcggtca cgctgcgcgt 9660 aaccaccaca cccgcgcgct taatgcgccg ctacagggcg cgtccattcg ccattcagga 9720 tcgaattaat tcttaat 9737 <210> 41 <211> 11671 <212> DNA <213> Artificial Sequence <220> <223> pAVQ-AS100KRib2-LacZ <400> 41 taacatcatc aataatatac cttattttgg attgaagcca atatgataat gagggggtgg 60 agtttgtgac gtggcgcggg gcgtgggaac ggggcgggtg acgtagtagt gtggcggaag 120 tgtgatgttg caagtgtggc ggaacacatg taagcgacgg atgtggcaaa agtgacgttt 180 ttggtgtgcg ccggtgtaca caggaagtga caattttcgc gcggttttag gcggatgttg 240 tagtaaattt gggcgtaacc gagtaagatt tggccatttt cgcgggaaaa ctgaataaga 300 ggaagtgaaa tctgaataat tttgtgttac tcatagcgcg taatactgcg atctatacat 360 tgaatcaata ttggcaatta gccatattag tcattggtta tatagcataa atcaatattg 420 gctattggcc attgcatacg ttgtatctat atcataatat gtacatttat attggctcat 480 gtccaatatg accgccatgt tgacattgat tattgactag ttattaatag taatcaatta 540 cggggtcatt agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg 600 gcccgcctgg ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc 660 ccatagtaac gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa 720 ctgcccactt ggcagtacat caagtgtatc atatgccaag tccgccccct attgacgtca 780 atgacggtaa atggcccgcc tggcattatg cccagtacat gaccttacgg gactttccta 840 cttggcagta catctacgta ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt 900 acaccaatgg gcgtggatag cggtttgact cacggggatt tccaagtctc caccccattg 960 acgtcaatgg gagtttgttt tggcaccaaa atcaacggga ctttccaaaa tgtcgtaata 1020 accccgcccc gttgacgcaa atgggcggta ggcgtgtacg gtgggaggtc tatataagca 1080 gagctcgttt agtgaaccgt cagatcctca ctctcttccg catcgctgtc tgcgagggcc 1140 agctgttggg ctcgcggttg aggacaaact cttcgcggtc tttccagtac tcttggatcg 1200 gaaacccgtc ggcctccgaa cggtactccg ccaccgaggg acctgagcca gtccgcatcg 1260 accggatcgg aaaacctctc gagaaaggcg tctaaccagt cacagtcgca aggtaggctg 1320 agcaccgtgg cgggcggcag cgggtggcgg tcggggttgt ttctggcgga ggtgctgctg 1380 atgatgtaat taaagtaggc ggtcttgagc cggcggatgg tcgaggtgag gtgtggcagg 1440 cttgagatcc agctgttggg gtgagtactc cctctcaaaa gcgggcatga cttctgcgct 1500 aagattgtca gtttccaaaa acgaggagga tttgatattc acctggcccg atctggccat 1560 acacttgagt gacaatgaca tccactttgc ctttctctcc acaggtgtcc actcccaggt 1620 ccaagtttgg aagatcccca tcaattacta cttgcttcct gtaggaatcc tctattgttg 1680 gatcatattc gtccacaaaa tgattctgaa ttagctgtat cgtcaaggca ctcttgcaag 1740 cttcatcatg gccgacagca aaagttatca ggcatgcacc tggtagctag tctttaaacc 1800 aatagattgc atcggtttaa aaggcaagac cgtcaaattg cgggaaaggg gtcaacagcc 1860 gttcagtacc aagtctcagg ggaaactttg agatggcctt gcaaagggta tggtaataag 1920 ctgacggaca tggtcctaac cacgcagcca agtcctaagt caacagatct tctgttgata 1980 tggatgcagt tcacagacta aatgtcggtc ggggaagatg tattcttctc ataagatata 2040 gtcggacctc tccttaatgg gagctagcgg atgaagtgat gcaacactgg agccgctggg 2100 aactaatttg tatgcgaaag tatattgatt agttttggag tactcgcgac atcatcacgt 2160 cgttttacaa cgtcgtttta caacgtcgtg actgggaaaa ccctggcgtt acccaactta 2220 atcgccttgc agcacatccc cctttcgcca gctggcgtaa tagcgaagag gcccgcaccg 2280 atcgcccttc ccaacagttg cgcagcctga atggcgaatg gcgctttgcc tggtttccgg 2340 caccagaagc ggtgccggaa agctggctgg agtgcgatct tcctgaggcc gatactgtcg 2400 tcgtcccctc aaactggcag atgcacggtt acgatgcgcc catctacacc aacgtgacct 2460 atcccattac ggtcaatccg ccgtttgttc ccacggagaa tccgacgggt tgttactcgc 2520 tcacatttaa tgttgatgaa agctggctac aggaaggcca gacgcgaatt atttttgatg 2580 gcgttaactc ggcgtttcat ctgtggtgca acgggcgctg ggtcggttac ggccaggaca 2640 gtcgtttgcc gtctgaattt gacctgagcg catttttacg cgccggagaa aaccgcctcg 2700 cggtgatggt gctgcgttgg agtgacggca gttatctgga agatcaggat atgtggcgga 2760 tgagcggcat tttccgtgac gtctcgttgc tgcataaacc gactacacaa atcagcgatt 2820 tccatgttgc cactcgcttt aatgatgatt tcagccgcgc tgtactggag gctgaagttc 2880 agatgtgcgg cgagttgcgt gactacctac gggtaacagt ttctttatgg cagggtgaaa 2940 cgcaggtcgc cagcggcacc gcgcctttcg gcggtgaaat tatcgatgag cgtggtggtt 3000 atgccgatcg cgtcacacta cgtctgaacg tcgaaaaccc gaaactgtgg agcgccgaaa 3060 tcccgaatct ctatcgtgcg gtggttgaac tgcacaccgc cgacggcacg ctgattgaag 3120 cagaagcctg cgatgtcggt ttccgcgagg tgcggattga aaatggtctg ctgctgctga 3180 acggcaagcc gttgctgatt cgaggcgtta accgtcacga gcatcatcct ctgcatggtc 3240 aggtcatgga tgagcagacg atggtgcagg atatcctgct gatgaagcag aacaacttta 3300 acgccgtgcg ctgttcgcat tatccgaacc atccgctgtg gtacacgctg tgcgaccgct 3360 acggcctgta tgtggtggat gaagccaata ttgaaaccca cggcatggtg ccaatgaatc 3420 gtctgaccga tgatccgcgc tggctaccgg cgatgagcga acgcgtaacg cgaatggtgc 3480 agcgcgatcg taatcacccg agtgtgatca tctggtcgct ggggaatgaa tcaggccacg 3540 gcgctaatca cgacgcgctg tatcgctgga tcaaatctgt cgatccttcc cgcccggtgc 3600 agtatgaagg cggcggagcc gacaccacgg ccaccgatat tatttgcccg atgtacgcgc 3660 gcgtggatga agaccagccc ttcccggctg tgccgaaatg gtccatcaaa aaatggcttt 3720 cgctacctgg agagacgcgc ccgctgatcc tttgcgaata cgcccacgcg atgggtaaca 3780 gtcttggcgg tttcgctaaa tactggcagg cgtttcgtca gtatccccgt ttacagggcg 3840 gcttcgtctg ggactgggtg gatcagtcgc tgattaaata tgatgaaaac ggcaacccgt 3900 ggtcggctta cggcggtgat tttggcgata cgccgaacga tcgccagttc tgtatgaacg 3960 gtctggtctt tgccgaccgc acgccgcatc cagcgctgac ggaagcaaaa caccagcagc 4020 agtttttcca gttccgttta tccgggcaaa ccatcgaagt gaccagcgaa tacctgttcc 4080 gtcatagcga taacgagctc ctgcactgga tggtggcgct ggatggtaag ccgctggcaa 4140 gcggtgaagt gcctctggat gtcgctccac aaggtaaaca gttgattgaa ctgcctgaac 4200 taccgcagcc ggagagcgcc gggcaactct ggctcacagt acgcgtagtg caaccgaacg 4260 cgaccgcatg gtcagaagcc gggcacatca gcgcctggca gcagtggcgt ctggcggaaa 4320 acctcagtgt gacgctcccc gccgcgtccc acgccatccc gcatctgacc accagcgaaa 4380 tggatttttg catcgagctg ggtaataagc gttggcaatt taaccgccag tcaggctttc 4440 tttcacagat gtggattggc gataaaaaac aactgctgac gccgctgcgc gatcagttca 4500 cccgtgcacc gctggataac gacattggcg taagtgaagc gacccgcatt gaccctaacg 4560 cctgggtcga acgctggaag gcggcgggcc attaccaggc cgaagcagcg ttgttgcagt 4620 gcacggcaga tacacttgct gatgcggtgc tgattacgac cgctcacgcg tggcagcatc 4680 aggggaaaac cttatttatc agccggaaaa cctaccggat tgatggtagt ggtcaaatgg 4740 cgattaccgt tgatgttgaa gtggcgagcg atacaccgca tccggcgcgg attggcctga 4800 actgccagct ggcgcaggta gcagagcggg taaactggct cggattaggg ccgcaagaaa 4860 actatcccga ccgccttact gccgcctgtt ttgaccgctg ggatctgcca ttgtcagaca 4920 tgtatacccc gtacgtcttc ccgagcgaaa acggtctgcg ctgcgggacg cgcgaattga 4980 attatggccc acaccagtgg cgcggcgact tccagttcaa catcagccgc tacagtcaac 5040 agcaactgat ggaaaccagc catcgccatc tgctgcacgc ggaagaaggc acatggctga 5100 atatcgacgg tttccatatg gggattggtg gcgacgactc ctggagcccg tcagtatcgg 5160 cggaattcca gctgagcgcc ggtcgctacc attaccagtt ggtctggtgt caaaaataat 5220 tcgaaagatc ccaacgaaaa gagagaccac atggtccttc ttgagtttgt aacagctgct 5280 gggattacac atggcatgga tgaactgtac aactgaggat cccccgacct cgacctctgg 5340 ctaataaagg aaatttattt tcattgcaat agtgtgttgg aattttttgt gtctctcact 5400 cggaaggaca tatgggaggg caaatcattt ggtcgagatc cctcggagat cggatctggg 5460 cgtggttaag ggtgggaaag aatatataag gtgggggtct tatgtagttt tgtatctgtt 5520 ttgcagcagc cgccgccgcc atgagcacca actcgtttga tggaagcatt gtgagctcat 5580 atttgacaac gcgcatgccc ccatgggccg gggtgcgtca gaatgtgatg ggctccagca 5640 ttgatggtcg ccccgtcctg cccgcaaact ctactacctt gacctacgag accgtgtctg 5700 gaacgccgtt ggagactgca gcctccgccg ccgcttcagc cgctgcagcc accgcccgcg 5760 ggattgtgac tgactttgct ttcctgagcc cgcttgcaag cagtgcagct tcccgttcat 5820 ccgcccgcga tgacaagttg acggctcttt tggcacaatt ggattctttg acccgggaac 5880 ttaatgtcgt ttctcagcag ctgttggatc tgcgccagca ggtttctgcc ctgaaggctt 5940 cctcccctcc caatgcggtt taaaacataa ataaaaaacc agactctgtt tggatttgga 6000 tcaagcaagt gtcttgctgt ctttatttag gggttttgcg cgcgcggtag gcccgggacc 6060 agcggtctcg gtcgttgagg gtcctgtgta ttttttccag gacgtggtaa aggtgactct 6120 ggatgttcag atacatgggc ataagcccgt ctctggggtg gaggtagcac cactgcagag 6180 cttcatgctg cggggtggtg ttgtagatga tccagtcgta gcaggagcgc tgggcgtggt 6240 gcctaaaaat gtctttcagt agcaagctga ttgccagggg caggcccttg gtgtaagtgt 6300 ttacaaagcg gttaagctgg gatgggtgca tacgtgggga tatgagatgc atcttggact 6360 gtatttttag gttggctatg ttcccagcca tatccctccg gggattcatg ttgtgcagaa 6420 ccaccagcac agtgtatccg gtgcacttgg gaaatttgtc atgtagctta gaaggaaatg 6480 cgtggaagaa cttggagacg cccttgtgac ctccaagatt ttccatgcat tcgtccataa 6540 tgatggcaat gggcccacgg gcggcggcct gggcgaagat atttctggga tcactaacgt 6600 catagttgtg ttccaggatg agatcgtcat aggccatttt tacaaagcgc gggcggaggg 6660 tgccagactg cggtataatg gttccatccg gcccaggggc gtagttaccc tcacagattt 6720 gcatttccca cgctttgagt tcagatgggg ggatcatgtc tacctgcggg gcgatgaaga 6780 aaacggtttc cggggtaggg gagatcagct gggaagaaag caggttcctg agcagctgcg 6840 acttaccgca gccggtgggc ccgtaaatca cacctattac cgggtgcaac tggtagttaa 6900 gagagctgca gctgccgtca tccctgagca ggggggccac ttcgttaagc atgtccctga 6960 ctcgcatgtt ttccctgacc aaatccgcca gaaggcgctc gccgcccagc gatagcagtt 7020 cttgcaagga agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggc atgcttttga 7080 gcgtttgacc aagcagttcc aggcggtccc acagctcggt cacctgctct acggcatctc 7140 gatccagcat atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacg gcagtagtcg 7200 gtgctcgtcc agacgggcca gggtcatgtc tttccacggg cgcagggtcc tcgtcagcgt 7260 agtctgggtc acggtgaagg ggtgcgctcc gggctgcgcg ctggccaggg tgcgcttgag 7320 gctggtcctg ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcgg ccaggtagca 7380 tttgaccatg gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgc gcagcttgcc 7440 cttggaggag gcgccgcacg aggggcagtg cagacttttg agggcgtaga gcttgggcgc 7500 gagaaatacc gattccgggg agtaggcatc cgcgccgcag gccccgcaga cggtctcgca 7560 ttccacgagc caggtgagct ctggccgttc ggggtcaaaa accaggtttc ccccatgctt 7620 tttgatgcgt ttcttacctc tggtttccat gagccggtgt ccacgctcgg tgacgaaaag 7680 gctgtccgtg tccccgtata cagacttgag agggagttta aacgaattca atagcttgtt 7740 gcatgggcgg cgatataaaa tgcaaggtgc tgctcaaaaa atcaggcaaa gcctcgcgca 7800 aaaaagaaag cacatcgtag tcatgctcat gcagataaag gcaggtaagc tccggaacca 7860 ccacagaaaa agacaccatt tttctctcaa acatgtctgc gggtttctgc ataaacacaa 7920 aataaaataa caaaaaaaca tttaaacatt agaagcctgt cttacaacag gaaaaacaac 7980 ccttataagc ataagacgga ctacggccat gccggcgtga ccgtaaaaaa actggtcacc 8040 gtgattaaaa agcaccaccg acagctcctc ggtcatgtcc ggagtcataa tgtaagactc 8100 ggtaaacaca tcaggttgat tcatcggtca gtgctaaaaa gcgaccgaaa tagcccgggg 8160 gaatacatac ccgcaggcgt agagacaaca ttacagcccc cataggaggt ataacaaaat 8220 taataggaga gaaaaacaca taaacacctg aaaaaccctc ctgcctaggc aaaatagcac 8280 cctcccgctc cagaacaaca tacagcgctt cacagcggca gcctaacagt cagccttacc 8340 agtaaaaaag aaaacctatt aaaaaaacac cactcgacac ggcaccagct caatcagtca 8400 cagtgtaaaa aagggccaag tgcagagcga gtatatatag gactaaaaaa tgacgtaacg 8460 gttaaagtcc acaaaaaaca cccagaaaac cgcacgcgaa cctacgccca gaaacgaaag 8520 ccaaaaaacc cacaacttcc tcaaatcgtc acttccgttt tcccacgtta cgtaacttcc 8580 cattttaaga aaactacaat tcccaacaca tacaagttac tccgccctaa aacctacgtc 8640 acccgccccg ttcccacgcc ccgcgccacg tcacaaactc caccccctca ttatcatatt 8700 ggcttcaatc caaaataagg tatattattg atgatgttaa ttaacatgca tggatccata 8760 tgcggtgtga aataccgcac agatgcgtaa ggagaaaata ccgcatcagg cgctcttccg 8820 cttcctcgct cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc 8880 actcaaaggc ggtaatacgg ttatccacag aatcagggga taacgcagga aagaacatgt 8940 gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc 9000 ataggctccg cccccctgac gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa 9060 acccgacagg actataaaga taccaggcgt ttccccctgg aagctccctc gtgcgctctc 9120 ctgttccgac cctgccgctt accggatacc tgtccgcctt tctcccttcg ggaagcgtgg 9180 cgctttctca tagctcacgc tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc 9240 tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc ggtaactatc 9300 gtcttgagtc caacccggta agacacgact tatcgccact ggcagcagcc actggtaaca 9360 ggattagcag agcgaggtat gtaggcggtg ctacagagtt cttgaagtgg tggcctaact 9420 acggctacac tagaaggaca gtatttggta tctgcgctct gctgaagcca gttaccttcg 9480 gaaaaagagt tggtagctct tgatccggca aacaaaccac cgctggtagc ggtggttttt 9540 ttgtttgcaa gcagcagatt acgcgcagaa aaaaaggatc tcaagaagat cctttgatct 9600 tttctacggg gtctgacgct cagtggaacg aaaactcacg ttaagggatt ttggtcatga 9660 gattatcaaa aaggatcttc acctagatcc ttttaaatta aaaatgaagt tttaaatcaa 9720 tctaaagtat atatgagtaa acttggtctg acagttacca atgcttaatc agtgaggcac 9780 ctatctcagc gatctgtcta tttcgttcat ccatagttgc ctgactcccc gtcgtgtaga 9840 taactacgat acgggagggc ttaccatctg gccccagtgc tgcaatgata ccgcgagacc 9900 cacgctcacc ggctccagat ttatcagcaa taaaccagcc agccggaagg gccgagcgca 9960 gaagtggtcc tgcaacttta tccgcctcca tccagtctat taattgttgc cgggaagcta 10020 gagtaagtag ttcgccagtt aatagtttgc gcaacgttgt tgccattgct gcagccatga 10080 gattatcaaa aaggatcttc acctagatcc ttttcacgta gaaagccagt ccgcagaaac 10140 ggtgctgacc ccggatgaat gtcagctact gggctatctg gacaagggaa aacgcaagcg 10200 caaagagaaa gcaggtagct tgcagtgggc ttacatggcg atagctagac tgggcggttt 10260 tatggacagc aagcgaaccg gaattgccag ctggggcgcc ctctggtaag gttgggaagc 10320 cctgcaaagt aaactggatg gctttctcgc cgccaaggat ctgatggcgc aggggatcaa 10380 gctctgatca agagacagga tgaggatcgt ttcgcatgat tgaacaagat ggattgcacg 10440 caggttctcc ggccgcttgg gtggagaggc tattcggcta tgactgggca caacagacaa 10500 tcggctgctc tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg gttctttttg 10560 tcaagaccga cctgtccggt gccctgaatg aactgcaaga cgaggcagcg cggctatcgt 10620 ggctggccac gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact gaagcgggaa 10680 gggactggct gctattgggc gaagtgccgg ggcaggatct cctgtcatct caccttgctc 10740 ctgccgagaa agtatccatc atggctgatg caatgcggcg gctgcatacg cttgatccgg 10800 ctacctgccc attcgaccac caagcgaaac atcgcatcga gcgagcacgt actcggatgg 10860 aagccggtct tgtcgatcag gatgatctgg acgaagagca tcaggggctc gcgccagccg 10920 aactgttcgc caggctcaag gcgagcatgc ccgacggcga ggatctcgtc gtgacccatg 10980 gcgatgcctg cttgccgaat atcatggtgg aaaatggccg cttttctgga ttcatcgact 11040 gtggccggct gggtgtggcg gaccgctatc aggacatagc gttggctacc cgtgatattg 11100 ctgaagagct tggcggcgaa tgggctgacc gcttcctcgt gctttacggt atcgccgctc 11160 ccgattcgca gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga attttgttaa 11220 aatttttgtt aaatcagctc attttttaac caataggccg aaatcggcaa catcccttat 11280 aaatcaaaag aatagaccgc gatagggttg agtgttgttc cagtttggaa caagagtcca 11340 ctattaaaga acgtggactc caacgtcaaa gggcgaaaaa ccgtctatca gggcgatggc 11400 ccactacgtg aaccatcacc caaatcaagt tttttgcggt cgaggtgccg taaagctcta 11460 aatcggaacc ctaaagggag cccccgattt agagcttgac ggggaaagcc ggcgaacgtg 11520 gcgagaaagg aagggaagaa agcgaaagga gcgggcgcta gggcgctggc aagtgtagcg 11580 gtcacgctgc gcgtaaccac cacacccgcg cgcttaatgc gccgctacag ggcgcgtcca 11640 ttcgccattc aggatcgaat taattcttaa t 11671 <210> 42 <211> 36428 <212> DNA <213> Artificial Sequence <220> <223> Ad-AS300KRib1-TK <400> 42 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13 140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14 100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25 140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32 100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33 120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta 33240 gttcatagcc catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc 33300 tgaccgccca acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg 33360 ccaataggga ctttccattg acgtcaatgg gtggagtatt tacggtaaac tgcccacttg 33420 gcagtacatc aagtgtatca tatgccaagt ccgcccccta ttgacgtcaa tgacggtaaa 33480 tggcccgcct ggcattatgc ccagtacatg accttacggg actttcctac ttggcagtac 33540 atctacgtat tagtcatcgc tattaccatg gtgatgcggt tttggcagta caccaatggg 33600 cgtggatagc ggtttgactc acggggattt ccaagtctcc accccattga cgtcaatggg 33660 agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat gtcgtaataa ccccgccccg 33720 ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct atataagcag agctcgttta 33780 gtgaaccgtc agatcctcac tctcttccgc atcgctgtct gcgagggcca gctgttgggc 33840 tcgcggttga ggacaaactc ttcgcggtct ttccagtact cttggatcgg aaacccgtcg 33900 gcctccgaac ggtactccgc caccgaggga cctgagccag tccgcatcga ccggatcgga 33960 aaacctctcg agaaaggcgt ctaaccagtc acagtcgcaa ggtaggctga gcaccgtggc 34020 gggcggcagc gggtggcggt cggggttgtt tctggcggag gtgctgctga tgatgtaatt 34080 aaagtaggcg gtcttgagcc ggcggatggt cgaggtgagg tgtggcaggc ttgagatcca 34140 gctgttgggg tgagtactcc ctctcaaaag cgggcatgac ttctgcgcta agattgtcag 34200 tttccaaaaa cgaggaggat ttgatattca cctggcccga tctggccata cacttgagtg 34260 acaatgacat ccactttgcc tttctctcca caggtgtcca ctcccaggtc caagtttgga 34320 agatccctac taggaccata ggtacatctt cagagtcctt aactctttta atttgttctc 34380 tataatggtg aatatcttca aatgatttag tattatttat ggcaaataca caaagaaagc 34440 cctccccagt cctcatgtac tggtccctca ttgcactgta ctcctcttga cctgctgtgt 34500 cgagaatatc caagagacag gtttctccat caattactac ttgcttcctg taggaatcct 34560 ctattgttgg atcatattcg tccacaaaat gattctgaat tagctgtatc gtcaaggcac 34620 tcttgcaagc ttcattatca gcagctaaaa gttatcaggc atgcacctgg tagctagtct 34680 ttaaaccaat agattgcatc ggtttaaaag gcaagaccgt caaattgcgg gaaaggggtc 34740 aacagccgtt cagtaccaag tctcagggga aactttgaga tggccttgca aagggtatgg 34800 taataagctg acggacatgg tcctaaccac gcagccaagt cctaagtcaa cagatcttct 34860 gttgatatgg atgcagttca cagactaaat gtcggtcggg gaagatgtat tcttctcata 34920 agatatagtc ggacctctcc ttaatgggag ctagcggatg aagtgatgca acactggagc 34980 cgctgggaac taatttgtat gcgaaagtat attgattagt tttggagtac tcgcgatgat 35040 cacgcttcgt acccctgcca tcaacacgcg tctgcgttcg accaggctgc gcgttctcgc 35 100 ggccatagca accgacgtac ggcgttgcgc cctcgccggc agcaagaagc cacggaagtc 35 160 cgcctggagc agaaaatgcc cacgctactg cgggtttata tagacggtcc tcacgggatg 35220 gggaaaacca ccaccacgca actgctggtg gccctgggtt cgcgcgacga tatcgtctac 35280 gtacccgagc cgatgactta ctggcaggtg ctgggggctt ccgagacaat cgcgaacatc 35340 tacaccacac aacaccgcct cgaccagggt gagatatcgg ccggggacgc ggcggtggta 35400 atgacaagcg cccagataac aatgggcatg ccttatgccg tgaccgacgc cgttctggct 35460 cctcatgtcg ggggggaggc tgggagttca catgccccgc ccccggccct caccctcatc 35520 ttcgaccgcc atcccatcgc cgccctcctg tgctacccgg ccgcgcgata ccttatgggc 35580 agcatgaccc cccaggccgt gctggcgttc gtggccctca tcccgccgac cttgcccggc 35640 acaaacatcg tgttgggggc ccttccggag gacagacaca tcgaccgcct ggccaaacgc 35700 cagcgccccg gcgagcggct tgacctggct atgctggccg cgattcgccg cgtttacggg 35760 ctgcttgcca atacggtgcg gtatctgcag ggcggcgggt cgtggtggga ggattgggga 35820 cagctttcgg ggacggccgt gccgccccag ggtgccgagc cccagagcaa cgcgggccca 35880 cgaccccata tcggggacac gttatttacc ctgtttcggg cccccgagtt gctggccccc 35940 aacggcgacc tgtataacgt gtttgcctgg gccttggacg tcttggccaa acgcctccgt 36000 cccatgcacg tctttatcct ggattacgac caatcgcccg ccggctgccg ggacgccctg 36060 ctgcaactta cctccgggat ggtccagacc cacgtcacca ccccaggctc cataccgacg 36120 atctgcgacc tggcgcgcac gtttgcccgg gagatggggg aggctaactg aagcttttcg 36180 aaggcgaaag atcccaacga aaagagagac cacatggtcc ttcttgagtt tgtaacagct 36240 gctgggatta cacatggcat ggatgaactg tacaactgag gatcccccga cctcgacctc 36300 tggctaataa aggaaattta ttttcattgc aatagtgtgt tggaattttt tgtgtctctc 36360 actcggaagg acatatggga gggcaaatca tttggtcgag atccctcgga gatcggatct 36420 gggcgtgg 36428 <210> 43 <211> 36226 <212> DNA <213> Artificial Sequence <220> <223> Ad-AS100KRib2-TK <400> 43 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13 140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14 100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25 140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32 100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33 120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta 33240 gttcatagcc catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc 33300 tgaccgccca acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg 33360 ccaataggga ctttccattg acgtcaatgg gtggagtatt tacggtaaac tgcccacttg 33420 gcagtacatc aagtgtatca tatgccaagt ccgcccccta ttgacgtcaa tgacggtaaa 33480 tggcccgcct ggcattatgc ccagtacatg accttacggg actttcctac ttggcagtac 33540 atctacgtat tagtcatcgc tattaccatg gtgatgcggt tttggcagta caccaatggg 33600 cgtggatagc ggtttgactc acggggattt ccaagtctcc accccattga cgtcaatggg 33660 agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat gtcgtaataa ccccgccccg 33720 ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct atataagcag agctcgttta 33780 gtgaaccgtc agatcctcac tctcttccgc atcgctgtct gcgagggcca gctgttgggc 33840 tcgcggttga ggacaaactc ttcgcggtct ttccagtact cttggatcgg aaacccgtcg 33900 gcctccgaac ggtactccgc caccgaggga cctgagccag tccgcatcga ccggatcgga 33960 aaacctctcg agaaaggcgt ctaaccagtc acagtcgcaa ggtaggctga gcaccgtggc 34020 gggcggcagc gggtggcggt cggggttgtt tctggcggag gtgctgctga tgatgtaatt 34080 aaagtaggcg gtcttgagcc ggcggatggt cgaggtgagg tgtggcaggc ttgagatcca 34140 gctgttgggg tgagtactcc ctctcaaaag cgggcatgac ttctgcgcta agattgtcag 34200 tttccaaaaa cgaggaggat ttgatattca cctggcccga tctggccata cacttgagtg 34260 acaatgacat ccactttgcc tttctctcca caggtgtcca ctcccaggtc caagtttgga 34320 agatccccat caattactac ttgcttcctg taggaatcct ctattgttgg atcatattcg 34380 tccacaaaat gattctgaat tagctgtatc gtcaaggcac tcttgcaagc ttcatcatgg 34440 ccgacagcaa aagttatcag gcatgcacct ggtagctagt ctttaaacca atagattgca 34500 tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg tcaacagccg ttcagtacca 34560 agtctcaggg gaaactttga gatggccttg caaagggtat ggtaataagc tgacggacat 34620 ggtcctaacc acgcagccaa gtcctaagtc aacagatctt ctgttgatat ggatgcagtt 34680 cacagactaa atgtcggtcg gggaagatgt attcttctca taagatatag tcggacctct 34740 ccttaatggg agctagcgga tgaagtgatg caacactgga gccgctggga actaatttgt 34800 atgcgaaagt atattgatta gttttggagt actcgcgaca tgatcacgct tcgtacccct 34860 gccatcaaca cgcgtctgcg ttcgaccagg ctgcgcgttc tcgcggccat agcaaccgac 34920 gtacggcgtt gcgccctcgc cggcagcaag aagccacgga agtccgcctg gagcagaaaa 34980 tgcccacgct actgcgggtt tatatagacg gtcctcacgg gatggggaaa accaccacca 35040 cgcaactgct ggtggccctg ggttcgcgcg acgatatcgt ctacgtaccc gagccgatga 35 100 cttactggca ggtgctgggg gcttccgaga caatcgcgaa catctacacc acacaacacc 35 160 gcctcgacca gggtgagata tcggccgggg acgcggcggt ggtaatgaca agcgcccaga 35220 taacaatggg catgccttat gccgtgaccg acgccgttct ggctcctcat gtcggggggg 35280 aggctgggag ttcacatgcc ccgcccccgg ccctcaccct catcttcgac cgccatccca 35340 tcgccgccct cctgtgctac ccggccgcgc gataccttat gggcagcatg accccccagg 35400 ccgtgctggc gttcgtggcc ctcatcccgc cgaccttgcc cggcacaaac atcgtgttgg 35460 gggcccttcc ggaggacaga cacatcgacc gcctggccaa acgccagcgc cccggcgagc 35520 ggcttgacct ggctatgctg gccgcgattc gccgcgttta cgggctgctt gccaatacgg 35580 tgcggtatct gcagggcggc gggtcgtggt gggaggattg gggacagctt tcggggacgg 35640 ccgtgccgcc ccagggtgcc gagccccaga gcaacgcggg cccacgaccc catatcgggg 35700 acacgttatt taccctgttt cgggcccccg agttgctggc ccccaacggc gacctgtata 35760 acgtgtttgc ctgggccttg gacgtcttgg ccaaacgcct ccgtcccatg cacgtcttta 35820 tcctggatta cgaccaatcg cccgccggct gccgggacgc cctgctgcaa cttacctccg 35880 ggatggtcca gacccacgtc accaccccag gctccatacc gacgatctgc gacctggcgc 35940 gcacgtttgc ccgggagatg ggggaggcta ataattcgaa ggcgaaagat cccaacgaaa 36000 agagagacca catggtcctt cttgagtttg taacagctgc tgggattaca catggcatgg 36060 atgaactgta caactgagga tcccccgacc tcgacctctg gctaataaag gaaatttatt 36120 ttcattgcaa tagtgtgttg gaattttttg tgtctctcac tcggaaggac atatgggagg 36180 gcaaatcatt tggtcgagat ccctcggaga tcggatctgg gcgtgg 36226 <210> 44 <211> 38160 <212> DNA <213> Artificial Sequence <220> <223> Ad-AS100Rib2-LacZ <400> 44 ttaagggtgg gaaagaatat ataaggtggg ggtcttatgt agttttgtat ctgttttgca 60 gcagccgccg ccgccatgag caccaactcg tttgatggaa gcattgtgag ctcatatttg 120 acaacgcgca tgcccccatg ggccggggtg cgtcagaatg tgatgggctc cagcattgat 180 ggtcgccccg tcctgcccgc aaactctact accttgacct acgagaccgt gtctggaacg 240 ccgttggaga ctgcagcctc cgccgccgct tcagccgctg cagccaccgc ccgcgggatt 300 gtgactgact ttgctttcct gagcccgctt gcaagcagtg cagcttcccg ttcatccgcc 360 cgcgatgaca agttgacggc tcttttggca caattggatt ctttgacccg ggaacttaat 420 gtcgtttctc agcagctgtt ggatctgcgc cagcaggttt ctgccctgaa ggcttcctcc 480 cctcccaatg cggtttaaaa cataaataaa aaaccagact ctgtttggat ttggatcaag 540 caagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc ggtaggcccg ggaccagcgg 600 tctcggtcgt tgagggtcct gtgtattttt tccaggacgt ggtaaaggtg actctggatg 660 ttcagataca tgggcataag cccgtctctg gggtggaggt agcaccactg cagagcttca 720 tgctgcgggg tggtgttgta gatgatccag tcgtagcagg agcgctgggc gtggtgccta 780 aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc ccttggtgta agtgtttaca 840 aagcggttaa gctgggatgg gtgcatacgt ggggatatga gatgcatctt ggactgtatt 900 tttaggttgg ctatgttccc agccatatcc ctccggggat tcatgttgtg cagaaccacc 960 agcacagtgt atccggtgca cttgggaaat ttgtcatgta gcttagaagg aaatgcgtgg 1020 aagaacttgg agacgccctt gtgacctcca agattttcca tgcattcgtc cataatgatg 1080 gcaatgggcc cacgggcggc ggcctgggcg aagatatttc tgggatcact aacgtcatag 1140 ttgtgttcca ggatgagatc gtcataggcc atttttacaa agcgcgggcg gagggtgcca 1200 gactgcggta taatggttcc atccggccca ggggcgtagt taccctcaca gatttgcatt 1260 tcccacgctt tgagttcaga tggggggatc atgtctacct gcggggcgat gaagaaaacg 1320 gtttccgggg taggggagat cagctgggaa gaaagcaggt tcctgagcag ctgcgactta 1380 ccgcagccgg tgggcccgta aatcacacct attaccgggt gcaactggta gttaagagag 1440 ctgcagctgc cgtcatccct gagcaggggg gccacttcgt taagcatgtc cctgactcgc 1500 atgttttccc tgaccaaatc cgccagaagg cgctcgccgc ccagcgatag cagttcttgc 1560 aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg taggcatgct tttgagcgtt 1620 tgaccaagca gttccaggcg gtcccacagc tcggtcacct gctctacggc atctcgatcc 1680 agcatatctc ctcgtttcgc gggttggggc ggctttcgct gtacggcagt agtcggtgct 1740 cgtccagacg ggccagggtc atgtctttcc acgggcgcag ggtcctcgtc agcgtagtct 1800 gggtcacggt gaaggggtgc gctccgggct gcgcgctggc cagggtgcgc ttgaggctgg 1860 tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc gtcggccagg tagcatttga 1920 ccatggtgtc atagtccagc ccctccgcgg cgtggccctt ggcgcgcagc ttgcccttgg 1980 aggaggcgcc gcacgagggg cagtgcagac ttttgagggc gtagagcttg ggcgcgagaa 2040 ataccgattc cggggagtag gcatccgcgc cgcaggcccc gcagacggtc tcgcattcca 2100 cgagccaggt gagctctggc cgttcggggt caaaaaccag gtttccccca tgctttttga 2160 tgcgtttctt acctctggtt tccatgagcc ggtgtccacg ctcggtgacg aaaaggctgt 2220 ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag cggtgttccg cggtcctcct 2280 cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt ccaggccagc acgaaggagg 2340 ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc cactcgctcc agggtgtgaa 2400 gacacatgtc gccctcttcg gcatcaagga aggtgattgg tttgtaggtg taggccacgt 2460 gaccgggtgt tcctgaaggg gggctataaa agggggtggg ggcgcgttcg tcctcactct 2520 cttccgcatc gctgtctgcg agggccagct gttggggtga gtactccctc tgaaaagcgg 2580 gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga ggaggatttg atattcacct 2640 ggcccgcggt gatgcctttg agggtggccg catccatctg gtcagaaaag acaatctttt 2700 tgttgtcaag cttggtggca aacgacccgt agagggcgtt ggacagcaac ttggcgatgg 2760 agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt ggccgcgatg tttagctgca 2820 cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt ggtgcgctcg tcgggcacca 2880 ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc aacgctggtg gctacctctc 2940 cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt gcgcgagcag aatggcggta 3000 gggggtctag ctgcgtctcg tccggggggt ctgcgtccac ggtaaagacc ccgggcagca 3060 ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc tagcgcctgc tgccatgcgc 3120 gggcggcaag cgcgcgctcg tatgggttga gtgggggacc ccatggcatg gggtgggtga 3180 gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag gggctctctg agtattccaa 3240 gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg cacgtaatcg tatagttcgt 3300 gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc gggctgctct gctcggaaga 3360 ctatctgcct gaagatggca tgtgagttgg atgatatggt tggacgctgg aagacgttga 3420 agctggcgtc tgtgagacct accgcgtcac gcacgaagga ggcgtaggag tcgcgcagct 3480 tgttgaccag ctcggcggtg acctgcacgt ctagggcgca gtagtccagg gtttccttga 3540 tgatgtcata cttatcctgt cccttttttt tccacagctc gcggttgagg acaaactctt 3600 cgcggtcttt ccagtactct tggatcggaa acccgtcggc ctccgaacgg taagagccta 3660 gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc cttttctacg ggtagcgcgt 3720 atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc aaaggtgtcc ctgaccatga 3780 ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc gccctgctcc cagagcaaaa 3840 agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa ggtgacatcg ttgaagagta 3900 tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa gggtcccggc acctcggaac 3960 ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa gccgttgatg ttgtggccca 4020 caatgtaaag ttccaagaag cgcgggatgc ccttgatgga aggcaatttt ttaagttcct 4080 cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga aagggcccag tctgcaagat 4140 gagggttgga agcgacgaat gagctccaca ggtcacgggc cattagcatt tgcaggtggt 4200 cgcgaaaggt cctaaactgg cgacctatgg ccattttttc tggggtgatg cagtagaagg 4260 taagcgggtc ttgttcccag cggtcccatc caaggttcgc ggctaggtct cgcgcggcag 4320 tcactagagg ctcatctccg ccgaacttca tgaccagcat gaagggcacg agctgcttcc 4380 caaaggcccc catccaagta taggtctcta catcgtaggt gacaaagaga cgctcggtgc 4440 gaggatgcga gccgatcggg aagaactgga tctcccgcca ccaattggag gagtggctat 4500 tgatgtggtg aaagtagaag tccctgcgac gggccgaaca ctcgtgctgg cttttgtaaa 4560 aacgtgcgca gtactggcag cggtgcacgg gctgtacatc ctgcacgagg ttgacctgac 4620 gaccgcgcac aaggaagcag agtgggaatt tgagcccctc gcctggcggg tttggctggt 4680 ggtcttctac ttcggctgct tgtccttgac cgtctggctg ctcgagggga gttacggtgg 4740 atcggaccac cacgccgcgc gagcccaaag tccagatgtc cgcgcgcggc ggtcggagct 4800 tgatgacaac atcgcgcaga tgggagctgt ccatggtctg gagctcccgc ggcgtcaggt 4860 caggcgggag ctcctgcagg tttacctcgc atagacgggt cagggcgcgg gctagatcca 4920 ggtgatacct aatttccagg ggctggttgg tggcggcgtc gatggcttgc aagaggccgc 4980 atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg ggccgcgggg gtgtccttgg 5040 atgatgcatc taaaagcggt gacgcgggcg agcccccgga ggtagggggg gctccggacc 5100 cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg ggcaggagct ggtgctgcgc 5160 gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc tcctgaatct ggcgcctctg 5220 cgtgaagacg acgggcccgg tgagcttgag cctgaaagag agttcgacag aatcaatttc 5280 ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg tctcctgagt tgtcttgata 5340 ggcgatctcg gccatgaact gctcgatctc ttcctcctgg agatctccgc gtccggctcg 5400 ctccacggtg gcggcgaggt cgttggaaat gcgggccatg agctgcgaga aggcgttgag 5460 gcctccctcg ttccagacgc ggctgtagac cacgccccct tcggcatcgc gggcgcgcat 5520 gaccacctgc gcgagattga gctccacgtg ccgggcgaag acggcgtagt ttcgcaggcg 5580 ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc acgaagaagt acataaccca 5640 gcgtcgcaac gtggattcgt tgatatcccc caaggcctca aggcgctcca tggcctcgta 5700 gaagtccacg gcgaagttga aaaactggga gttgcgcgcc gacacggtta actcctcctc 5760 cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg cgctcaaagg ctacaggggc 5820 ctcttcttct tcttcaatct cctcttccat aagggcctcc ccttcttctt cttctggcgg 5880 cggtggggga ggggggacac ggcggcgacg acggcgcacc gggaggcggt cgacaaagcg 5940 ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg acggcgcggc cgttctcgcg 6000 ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta tgggttggcg gggggctgcc 6060 atgcggcagg gatacggcgc taacgatgca tctcaacaat tgttgtgtag gtactccgcc 6120 gccgagggac ctgagcgagt ccgcatcgac cggatcggaa aacctctcga gaaaggcgtc 6180 taaccagtca cagtcgcaag gtaggctgag caccgtggcg ggcggcagcg ggcggcggtc 6240 ggggttgttt ctggcggagg tgctgctgat gatgtaatta aagtaggcgg tcttgagacg 6300 gcggatggtc gacagaagca ccatgtcctt gggtccggcc tgctgaatgc gcaggcggtc 6360 ggccatgccc caggcttcgt tttgacatcg gcgcaggtct ttgtagtagt cttgcatgag 6420 cctttctacc ggcacttctt cttctccttc ctcttgtcct gcatctcttg catctatcgc 6480 tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt cctcccatgc gtgtgacccc 6540 gaagcccctc atcggctgaa gcagggctag gtcggcgaca acgcgctcgg ctaatatggc 6600 ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg tccacaaagc ggtggtatgc 6660 gcccgtgttg atggtgtaag tgcagttggc cataacggac cagttaacgg tctggtgacc 6720 cggctgcgag agctcggtgt acctgagacg cgagtaagcc ctcgagtcaa atacgtagtc 6780 gttgcaagtc cgcaccaggt actggtatcc caccaaaaag tgcggcggcg gctggcggta 6840 gaggggccag cgtagggtgg ccggggctcc gggggcgaga tcttccaaca taaggcgatg 6900 atatccgtag atgtacctgg acatccaggt gatgccggcg gcggtggtgg aggcgcgcgg 6960 aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa aagtgctcca tggtcgggac 7020 gctctggccg gtcaggcgcg cgcaatcgtt gacgctctac cgtgcaaaag gagagcctgt 7080 aagcgggcac tcttccgtgg tctggtggat aaattcgcaa gggtatcatg gcggacgacc 7140 ggggttcgag ccccgtatcc ggccgtccgc cgtgatccat gcggttaccg cccgcgtgtc 7200 gaacccaggt gtgcgacgtc agacaacggg ggagtgctcc ttttggcttc cttccaggcg 7260 cggcggctgc tgcgctagct tttttggcca ctggccgcgc gcagcgtaag cggttaggct 7320 ggaaagcgaa agcattaagt ggctcgctcc ctgtagccgg agggttattt tccaagggtt 7380 gagtcgcggg acccccggtt cgagtctcgg accggccgga ctgcggcgaa cgggggtttg 7440 cctccccgtc atgcaagacc ccgcttgcaa attcctccgg aaacagggac gagccccttt 7500 tttgcttttc ccagatgcat ccggtgctgc ggcagatgcg cccccctcct cagcagcggc 7560 aagagcaaga gcagcggcag acatgcaggg caccctcccc tcctcctacc gcgtcaggag 7620 gggcgacatc cgcggttgac gcggcagcag atggtgatta cgaacccccg cggcgccggg 7680 cccggcacta cctggacttg gaggagggcg agggcctggc gcggctagga gcgccctctc 7740 ctgagcggta cccaagggtg cagctgaagc gtgatacgcg tgaggcgtac gtgccgcggc 7800 agaacctgtt tcgcgaccgc gagggagagg agcccgagga gatgcgggat cgaaagttcc 7860 acgcagggcg cgagctgcgg catggcctga atcgcgagcg gttgctgcgc gaggaggact 7920 ttgagcccga cgcgcgaacc gggattagtc ccgcgcgcgc acacgtggcg gccgccgacc 7980 tggtaaccgc atacgagcag acggtgaacc aggagattaa ctttcaaaaa agctttaaca 8040 accacgtgcg tacgcttgtg gcgcgcgagg aggtggctat aggactgatg catctgtggg 8100 actttgtaag cgcgctggag caaaacccaa atagcaagcc gctcatggcg cagctgttcc 8160 ttatagtgca gcacagcagg gacaacgagg cattcaggga tgcgctgcta aacatagtag 8220 agcccgaggg ccgctggctg ctcgatttga taaacatcct gcagagcata gtggtgcagg 8280 agcgcagctt gagcctggct gacaaggtgg ccgccatcaa ctattccatg cttagcctgg 8340 gcaagtttta cgcccgcaag atataccata ccccttacgt tcccatagac aaggaggtaa 8400 agatcgaggg gttctacatg cgcatggcgc tgaaggtgct taccttgagc gacgacctgg 8460 gcgtttatcg caacgagcgc atccacaagg ccgtgagcgt gagccggcgg cgcgagctca 8520 gcgaccgcga gctgatgcac agcctgcaaa gggccctggc tggcacgggc agcggcgata 8580 gagaggccga gtcctacttt gacgcgggcg ctgacctgcg ctgggcccca agccgacgcg 8640 ccctggaggc agctggggcc ggacctgggc tggcggtggc acccgcgcgc gctggcaacg 8700 tcggcggcgt ggaggaatat gacgaggacg atgagtacga gccagaggac ggcgagtact 8760 aagcggtgat gtttctgatc agatgatgca agacgcaacg gacccggcgg tgcgggcggc 8820 gctgcagagc cagccgtccg gccttaactc cacggacgac tggcgccagg tcatggaccg 8880 catcatgtcg ctgactgcgc gcaatcctga cgcgttccgg cagcagccgc aggccaaccg 8940 gctctccgca attctggaag cggtggtccc ggcgcgcgca aaccccacgc acgagaaggt 9000 gctggcgatc gtaaacgcgc tggccgaaaa cagggccatc cggcccgacg aggccggcct 9060 ggtctacgac gcgctgcttc agcgcgtggc tcgttacaac agcggcaacg tgcagaccaa 9120 cctggaccgg ctggtggggg atgtgcgcga ggccgtggcg cagcgtgagc gcgcgcagca 9180 gcagggcaac ctgggctcca tggttgcact aaacgccttc ctgagtacac agcccgccaa 9240 cgtgccgcgg ggacaggagg actacaccaa ctttgtgagc gcactgcggc taatggtgac 9300 tgagacaccg caaagtgagg tgtaccagtc tgggccagac tattttttcc agaccagtag 9360 acaaggcctg cagaccgtaa acctgagcca ggctttcaaa aacttgcagg ggctgtgggg 9420 ggtgcgggct cccacaggcg accgcgcgac cgtgtctagc ttgctgacgc ccaactcgcg 9480 cctgttgctg ctgctaatag cgcccttcac ggacagtggc agcgtgtccc gggacacata 9540 cctaggtcac ttgctgacac tgtaccgcga ggccataggt caggcgcatg tggacgagca 9600 tactttccag gagattacaa gtgtcagccg cgcgctgggg caggaggaca cgggcagcct 9660 ggaggcaacc ctaaactacc tgctgaccaa ccggcggcag aagatcccct cgttgcacag 9720 tttaaacagc gaggaggagc gcattttgcg ctacgtgcag cagagcgtga gccttaacct 9780 gatgcgcgac ggggtaacgc ccagcgtggc gctggacatg accgcgcgca acatggaacc 9840 gggcatgtat gcctcaaacc ggccgtttat caaccgccta atggactact tgcatcgcgc 9900 ggccgccgtg aaccccgagt atttcaccaa tgccatcttg aacccgcact ggctaccgcc 9960 ccctggtttc tacaccgggg gattcgaggt gcccgagggt aacgatggat tcctctggga 10020 cgacatagac gacagcgtgt tttccccgca accgcagacc ctgctagagt tgcaacagcg 10080 cgagcaggca gaggcggcgc tgcgaaagga aagcttccgc aggccaagca gcttgtccga 10140 tctaggcgct gcggccccgc ggtcagatgc tagtagccca tttccaagct tgatagggtc 10200 tcttaccagc actcgcacca cccgcccgcg cctgctgggc gaggaggagt acctaaacaa 10260 ctcgctgctg cagccgcagc gcgaaaaaaa cctgcctccg gcatttccca acaacgggat 10320 agagagccta gtggacaaga tgagtagatg gaagacgtac gcgcaggagc acagggacgt 10380 gccaggcccg cgcccgccca cccgtcgtca aaggcacgac cgtcagcggg gtctggtgtg 10440 ggaggacgat gactcggcag acgacagcag cgtcctggat ttgggaggga gtggcaaccc 10500 gtttgcgcac cttcgcccca ggctggggag aatgttttaa aaaaaaaaaa gcatgatgca 10560 aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 10620 atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 10680 gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 10740 gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 10800 gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 10860 tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 10920 tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 10980 ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 11040 aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 11100 ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 11160 atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 11220 gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 11280 cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 11340 attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 11400 atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 11460 ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 11520 gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 11580 tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 11640 ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 11700 gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 11760 cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 11820 acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 11880 tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 11940 ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 12000 ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 12060 gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 12120 gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 12180 cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 12240 gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 12300 gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 12360 cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 12420 aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 12480 cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 12540 gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 12600 accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 12660 cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 12720 cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 12780 attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 12840 agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 12900 ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 12960 gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 13020 aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 13080 gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 13 140 gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 13200 cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 13260 cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 13320 gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 13380 gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 13440 ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 13500 tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 13560 gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 13620 aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 13680 agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 13740 gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 13800 gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg cggttcgagg 13860 aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 13920 acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 13980 accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 14040 gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 14 100 cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 14160 ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 14220 cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 14280 cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 14340 gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 14400 atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 14460 ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 14520 catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 14580 ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 14640 ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 14700 aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 14760 agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 14820 ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 14880 agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 14940 cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 15000 cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 15060 gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 15120 gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 15180 tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 15240 gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 15300 tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 15360 gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 15420 ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 15480 gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 15540 tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 15600 acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 15660 actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 15720 gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 15780 gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 15840 attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 15900 acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 15960 gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 16020 aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 16080 gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 16140 aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 16200 catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 16260 tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 16320 tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 16380 gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 16440 gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 16500 agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 16560 ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 16620 tgggaaaaag atgctacaga attttcagat aaaaatgaaa taagagttgg aaataatttt 16680 gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 16740 ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 16800 aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 16860 aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 16920 cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 16980 cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 17040 tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 17100 aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 17160 ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 17220 aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 17280 aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 17340 gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 17400 tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 17460 aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 17520 acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 17580 tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 17640 cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 17700 cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 17760 atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 17820 ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 17880 attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 17940 tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 18000 cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 18060 ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 18120 gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 18180 caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 18240 ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 18300 cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 18360 ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 18420 tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 18480 gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 18540 aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 18600 actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 18660 actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 18720 acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 18780 ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 18840 aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 18900 gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 18960 cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 19020 cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 19080 ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 19140 ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 19200 cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 19260 gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 19320 gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 19380 tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 19440 tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 19500 tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 19560 gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 19620 tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 19680 gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 19740 gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 19800 tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 19860 ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 19920 ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 19980 gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 20040 tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 20100 ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 20160 cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 20220 gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 20280 gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 20340 actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 20400 acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 20460 gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 20520 agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 20580 ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 20640 aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 20700 gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 20760 aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 20820 tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 20880 tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 20940 taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 21000 ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 21060 tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 21120 gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 21180 gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 21240 actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 21300 gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 21360 cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 21420 aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 21480 aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 21540 ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 21600 tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 21660 ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 21720 ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 21780 gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 21840 tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 21900 ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 21960 gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 22020 actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 22080 ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 22140 accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 22200 gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 22260 tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 22320 cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 22380 cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 22440 aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 22500 ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 22560 ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 22620 agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 22680 cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 22740 ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 22800 gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 22860 ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 22920 gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 22980 tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 23040 cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 23100 gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 23160 taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 23220 ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 23280 agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 23340 ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 23400 ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 23460 gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 23520 taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 23580 aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccattat 23640 gagcaaggaa attcccacgc cctacatgtg gagttaccag ccacaaatgg gacttgcggc 23700 tggagctgcc caagactact caacccgaat aaactacatg agcgcgggac cccacatgat 23760 atcccgggtc aacggaatcc gcgcccaccg aaaccgaatt ctcttggaac aggcggctat 23820 taccaccaca cctcgtaata accttaatcc ccgtagttgg cccgctgccc tggtgtacca 23880 ggaaagtccc gctcccacca ctgtggtact tcccagagac gcccaggccg aagttcagat 23940 gactaactca ggggcgcagc ttgcgggcgg ctttcgtcac agggtgcggt cgcccgggca 24000 gggtataact cacctgacaa tcagagggcg aggtattcag ctcaacgacg agtcggtgag 24060 ctcctcgctt ggtctccgtc cggacgggac atttcagatc ggcggcgccg gccgtccttc 24120 attcacgcct cgtcaggcaa tcctaactct gcagacctcg tcctctgagc cgcgctctgg 24180 aggcattgga actctgcaat ttattgagga gtttgtgcca tcggtctact ttaacccctt 24240 ctcgggacct cccggccact atccggatca atttattcct aactttgacg cggtaaagga 24300 ctcggcggac ggctacgact gaatgttaag tggagaggca gagcaactgc gcctgaaaca 24360 cctggtccac tgtcgccgcc acaagtgctt tgcccgcgac tccggtgagt tttgctactt 24420 tgaattgccc gaggatcata tcgagggccc ggcgcacggc gtccggctta ccgcccaggg 24480 agagcttgcc cgtagcctga ttcgggagtt tacccagcgc cccctgctag ttgagcggga 24540 caggggaccc tgtgttctca ctgtgatttg caactgtcct aaccttggat tacatcaaga 24600 tcctctagtt ataactagag tacccgggga tcttattccc tttaactaat aaaaaaaaat 24660 aataaagcat cacttactta aaatcagtta gcaaatttct gtccagttta ttcagcagca 24720 cctccttgcc ctcctcccag ctctggtatt gcagcttcct cctggctgca aactttctcc 24780 acaatctaaa tggaatgtca gtttcctcct gttcctgtcc atccgcaccc actatcttca 24840 tgttgttgca gatgaagcgc gcaagaccgt ctgaagatac cttcaacccc gtgtatccat 24900 atgacacgga aaccggtcct ccaactgtgc cttttcttac tcctcccttt gtatccccca 24960 atgggtttca agagagtccc cctggggtac tctctttgcg cctatccgaa cctctagtta 25020 cctccaatgg catgcttgcg ctcaaaatgg gcaacggcct ctctctggac gaggccggca 25080 accttacctc ccaaaatgta accactgtga gcccacctct caaaaaaacc aagtcaaaca 25 140 taaacctgga aatatctgca cccctcacag ttacctcaga agccctaact gtggctgccg 25200 ccgcacctct aatggtcgcg ggcaacacac tcaccatgca atcacaggcc ccgctaaccg 25260 tgcacgactc caaacttagc attgccaccc aaggacccct cacagtgtca gaaggaaagc 25320 tagccctgca aacatcaggc cccctcacca ccaccgatag cagtaccctt actatcactg 25380 cctcaccccc tctaactact gccactggta gcttgggcat tgacttgaaa gagcccattt 25440 atacacaaaa tggaaaacta ggactaaagt acggggctcc tttgcatgta acagacgacc 25500 taaacacttt gaccgtagca actggtccag gtgtgactat taataatact tccttgcaaa 25560 ctaaagttac tggagccttg ggttttgatt cacaaggcaa tatgcaactt aatgtagcag 25620 gaggactaag gattgattct caaaacagac gccttatact tgatgttagt tatccgtttg 25680 atgctcaaaa ccaactaaat ctaagactag gacagggccc tctttttata aactcagccc 25740 acaacttgga tattaactac aacaaaggcc tttacttgtt tacagcttca aacaattcca 25800 aaaagcttga ggttaaccta agcactgcca aggggttgat gtttgacgct acagccatag 25860 ccattaatgc aggagatggg cttgaatttg gttcacctaa tgcaccaaac acaaatcccc 25920 tcaaaacaaa aattggccat ggcctagaat ttgattcaaa caaggctatg gttcctaaac 25980 taggaactgg ccttagtttt gacagcacag gtgccattac agtaggaaac aaaaataatg 26040 ataagctaac tttgtggacc acaccagctc catctcctaa ctgtagacta aatgcagaga 26100 aagatgctaa actcactttg gtcttaacaa aatgtggcag tcaaatactt gctacagttt 26160 cagttttggc tgttaaaggc agtttggctc caatatctgg aacagttcaa agtgctcatc 26220 ttattataag atttgacgaa aatggagtgc tactaaacaa ttccttcctg gacccagaat 26280 attggaactt tagaaatgga gatcttactg aaggcacagc ctatacaaac gctgttggat 26340 ttatgcctaa cctatcagct tatccaaaat ctcacggtaa aactgccaaa agtaacattg 26400 tcagtcaagt ttacttaaac ggagacaaaa ctaaacctgt aacactaacc attacactaa 26460 acggtacaca ggaaacagga gacacaactc caagtgcata ctctatgtca ttttcatggg 26520 actggtctgg ccacaactac attaatgaaa tatttgccac atcctcttac actttttcat 26580 acattgccca agaataaaga atcgtttgtg ttatgtttca acgtgtttat ttttcaattg 26640 cagaaaattt caagtcattt ttcattcagt agtatagccc caccaccaca tagcttatac 26700 agatcaccgt accttaatca aactcacaga accctagtat tcaacctgcc acctccctcc 26760 caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 26820 gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 26880 tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 26940 tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 27000 gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 27060 gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 27120 tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 27180 cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 27240 aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 27300 tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 27360 ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 27420 tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 27480 gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 27540 ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 27600 cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 27660 tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 27720 attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 27780 tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 27840 cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 27900 aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 27960 tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 28020 ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 28080 cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 28140 tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 28200 ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 28260 taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 28320 agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 28380 caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 28440 gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 28500 agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 28560 cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 28620 atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacct tgacaaaaga 28680 acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 28740 agctttcaat agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat 28800 caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc 28860 aggtaagctc cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg 28920 gtttctgcat aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct 28980 tacaacagga aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc 29040 gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg 29100 agtcataatg taagactcgg taaacacatc aggttgattc atcggtcagt gctaaaaagc 29160 gaccgaaata gcccggggga atacataccc gcaggcgtag agacaacatt acagccccca 29220 taggaggtat aacaaaatta ataggagaga aaaacacata aacacctgaa aaaccctcct 29280 gcctaggcaa aatagcaccc tcccgctcca gaacaacata cagcgcttca cagcggcagc 29340 ctaacagtca gccttaccag taaaaaagaa aacctattaa aaaaacacca ctcgacacgg 29400 caccagctca atcagtcaca gtgtaaaaaa gggccaagtg cagagcgagt atatatagga 29460 ctaaaaaatg acgtaacggt taaagtccac aaaaaacacc cagaaaaccg cacgcgaacc 29520 tacgcccaga aacgaaagcc aaaaaaccca caacttcctc aaatcgtcac ttccgttttc 29580 ccacgttacg taacttccca ttttaagaaa actacaattc ccaacacata caagttactc 29640 cgccctaaaa cctacgtcac ccgccccgtt cccacgcccc gcgccacgtc acaaactcca 29700 ccccctcatt atcatattgg cttcaatcca aaataaggta tattattgat gatgttaatt 29760 aacatgcatg gatccatatg cggtgtgaaa taccgcacag atgcgtaagg agaaaatacc 29820 gcatcaggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 29880 ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 29940 acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 30000 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 30060 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 30120 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 30180 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 30240 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 30300 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 30360 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 30420 tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 30480 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 30540 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 30600 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 30660 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 30720 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 30780 gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 30840 gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 30900 caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 30960 ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 31020 attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 31080 ccattgctgc agccatgaga ttatcaaaaa ggatcttcac ctagatcctt ttcacgtaga 31140 aagccagtcc gcagaaacgg tgctgacccc ggatgaatgt cagctactgg gctatctgga 31200 caagggaaaa cgcaagcgca aagagaaagc aggtagcttg cagtgggctt acatggcgat 31260 agctagactg ggcggtttta tggacagcaa gcgaaccgga attgccagct ggggcgccct 31320 ctggtaaggt tgggaagccc tgcaaagtaa actggatggc tttctcgccg ccaaggatct 31380 gatggcgcag gggatcaagc tctgatcaag agacaggatg aggatcgttt cgcatgattg 31440 aacaagatgg attgcacgca ggttctccgg ccgcttgggt ggagaggcta ttcggctatg 31500 actgggcaca acagacaatc ggctgctctg atgccgccgt gttccggctg tcagcgcagg 31560 ggcgcccggt tctttttgtc aagaccgacc tgtccggtgc cctgaatgaa ctgcaagacg 31620 aggcagcgcg gctatcgtgg ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg 31680 ttgtcactga agcgggaagg gactggctgc tattgggcga agtgccgggg caggatctcc 31740 tgtcatctca ccttgctcct gccgagaaag tatccatcat ggctgatgca atgcggcggc 31800 tgcatacgct tgatccggct acctgcccat tcgaccacca agcgaaacat cgcatcgagc 31860 gagcacgtac tcggatggaa gccggtcttg tcgatcagga tgatctggac gaagagcatc 31920 aggggctcgc gccagccgaa ctgttcgcca ggctcaaggc gagcatgccc gacggcgagg 31980 atctcgtcgt gacccatggc gatgcctgct tgccgaatat catggtggaa aatggccgct 32040 tttctggatt catcgactgt ggccggctgg gtgtggcgga ccgctatcag gacatagcgt 32 100 tggctacccg tgatattgct gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc 32160 tttacggtat cgccgctccc gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt 32220 tcttctgaat tttgttaaaa tttttgttaa atcagctcat tttttaacca ataggccgaa 32280 atcggcaaca tcccttataa atcaaaagaa tagaccgcga tagggttgag tgttgttcca 32340 gtttggaaca agagtccact attaaagaac gtggactcca acgtcaaagg gcgaaaaacc 32400 gtctatcagg gcgatggccc actacgtgaa ccatcaccca aatcaagttt tttgcggtcg 32460 aggtgccgta aagctctaaa tcggaaccct aaagggagcc cccgatttag agcttgacgg 32520 ggaaagccgg cgaacgtggc gagaaaggaa gggaagaaag cgaaaggagc gggcgctagg 32580 gcgctggcaa gtgtagcggt cacgctgcgc gtaaccacca cacccgcgcg cttaatgcgc 32640 cgctacaggg cgcgtccatt cgccattcag gatcgaatta attcttaatt aacatcatca 32700 ataatatacc ttattttgga ttgaagccaa tatgataatg agggggtgga gtttgtgacg 32760 tggcgcgggg cgtgggaacg gggcgggtga cgtagtagtg tggcggaagt gtgatgttgc 32820 aagtgtggcg gaacacatgt aagcgacgga tgtggcaaaa gtgacgtttt tggtgtgcgc 32880 cggtgtacac aggaagtgac aattttcgcg cggttttagg cggatgttgt agtaaatttg 32940 ggcgtaaccg agtaagattt ggccattttc gcgggaaaac tgaataagag gaagtgaaat 33000 ctgaataatt ttgtgttact catagcgcgt aatactgcga tctatacatt gaatcaatat 33060 tggcaattag ccatattagt cattggttat atagcataaa tcaatattgg ctattggcca 33 120 ttgcatacgt tgtatctata tcataatatg tacatttata ttggctcatg tccaatatga 33180 ccgccatgtt gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta 33240 gttcatagcc catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc 33300 tgaccgccca acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg 33360 ccaataggga ctttccattg acgtcaatgg gtggagtatt tacggtaaac tgcccacttg 33420 gcagtacatc aagtgtatca tatgccaagt ccgcccccta ttgacgtcaa tgacggtaaa 33480 tggcccgcct ggcattatgc ccagtacatg accttacggg actttcctac ttggcagtac 33540 atctacgtat tagtcatcgc tattaccatg gtgatgcggt tttggcagta caccaatggg 33600 cgtggatagc ggtttgactc acggggattt ccaagtctcc accccattga cgtcaatggg 33660 agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat gtcgtaataa ccccgccccg 33720 ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct atataagcag agctcgttta 33780 gtgaaccgtc agatcctcac tctcttccgc atcgctgtct gcgagggcca gctgttgggc 33840 tcgcggttga ggacaaactc ttcgcggtct ttccagtact cttggatcgg aaacccgtcg 33900 gcctccgaac ggtactccgc caccgaggga cctgagccag tccgcatcga ccggatcgga 33960 aaacctctcg agaaaggcgt ctaaccagtc acagtcgcaa ggtaggctga gcaccgtggc 34020 gggcggcagc gggtggcggt cggggttgtt tctggcggag gtgctgctga tgatgtaatt 34080 aaagtaggcg gtcttgagcc ggcggatggt cgaggtgagg tgtggcaggc ttgagatcca 34140 gctgttgggg tgagtactcc ctctcaaaag cgggcatgac ttctgcgcta agattgtcag 34200 tttccaaaaa cgaggaggat ttgatattca cctggcccga tctggccata cacttgagtg 34260 acaatgacat ccactttgcc tttctctcca caggtgtcca ctcccaggtc caagtttgga 34320 agatccccat caattactac ttgcttcctg taggaatcct ctattgttgg atcatattcg 34380 tccacaaaat gattctgaat tagctgtatc gtcaaggcac tcttgcaagc ttcatcatgg 34440 ccgacagcaa aagttatcag gcatgcacct ggtagctagt ctttaaacca atagattgca 34500 tcggtttaaa aggcaagacc gtcaaattgc gggaaagggg tcaacagccg ttcagtacca 34560 agtctcaggg gaaactttga gatggccttg caaagggtat ggtaataagc tgacggacat 34620 ggtcctaacc acgcagccaa gtcctaagtc aacagatctt ctgttgatat ggatgcagtt 34680 cacagactaa atgtcggtcg gggaagatgt attcttctca taagatatag tcggacctct 34740 ccttaatggg agctagcgga tgaagtgatg caacactgga gccgctggga actaatttgt 34800 atgcgaaagt atattgatta gttttggagt actcgcgaca tcatcacgtc gttttacaac 34860 gtcgttttac aacgtcgtga ctgggaaaac cctggcgtta cccaacttaa tcgccttgca 34920 gcacatcccc ctttcgccag ctggcgtaat agcgaagagg cccgcaccga tcgcccttcc 34980 caacagttgc gcagcctgaa tggcgaatgg cgctttgcct ggtttccggc accagaagcg 35040 gtgccggaaa gctggctgga gtgcgatctt cctgaggccg atactgtcgt cgtcccctca 35 100 aactggcaga tgcacggtta cgatgcgccc atctacacca acgtgaccta tcccattacg 35 160 gtcaatccgc cgtttgttcc cacggagaat ccgacgggtt gttactcgct cacatttaat 35220 gttgatgaaa gctggctaca ggaaggccag acgcgaatta tttttgatgg cgttaactcg 35280 gcgtttcatc tgtggtgcaa cgggcgctgg gtcggttacg gccaggacag tcgtttgccg 35340 tctgaatttg acctgagcgc atttttacgc gccggagaaa accgcctcgc ggtgatggtg 35400 ctgcgttgga gtgacggcag ttatctggaa gatcaggata tgtggcggat gagcggcatt 35460 ttccgtgacg tctcgttgct gcataaaccg actacacaaa tcagcgattt ccatgttgcc 35520 actcgcttta atgatgattt cagccgcgct gtactggagg ctgaagttca gatgtgcggc 35580 gagttgcgtg actacctacg ggtaacagtt tctttatggc agggtgaaac gcaggtcgcc 35640 agcggcaccg cgcctttcgg cggtgaaatt atcgatgagc gtggtggtta tgccgatcgc 35700 gtcacactac gtctgaacgt cgaaaacccg aaactgtgga gcgccgaaat cccgaatctc 35760 tatcgtgcgg tggttgaact gcacaccgcc gacggcacgc tgattgaagc agaagcctgc 35820 gatgtcggtt tccgcgaggt gcggattgaa aatggtctgc tgctgctgaa cggcaagccg 35880 ttgctgattc gaggcgttaa ccgtcacgag catcatcctc tgcatggtca ggtcatggat 35940 gagcagacga tggtgcagga tatcctgctg atgaagcaga acaactttaa cgccgtgcgc 36000 tgttcgcatt atccgaacca tccgctgtgg tacacgctgt gcgaccgcta cggcctgtat 36060 gtggtggatg aagccaatat tgaaacccac ggcatggtgc caatgaatcg tctgaccgat 36120 gatccgcgct ggctaccggc gatgagcgaa cgcgtaacgc gaatggtgca gcgcgatcgt 36180 aatcacccga gtgtgatcat ctggtcgctg gggaatgaat caggccacgg cgctaatcac 36240 gacgcgctgt atcgctggat caaatctgtc gatccttccc gcccggtgca gtatgaaggc 36300 ggcggagccg acaccacggc caccgatatt atttgcccga tgtacgcgcg cgtggatgaa 36360 gaccagccct tcccggctgt gccgaaatgg tccatcaaaa aatggctttc gctacctgga 36420 gagacgcgcc cgctgatcct ttgcgaatac gcccacgcga tgggtaacag tcttggcggt 36480 ttcgctaaat actggcaggc gtttcgtcag tatccccgtt tacagggcgg cttcgtctgg 36540 gactgggtgg atcagtcgct gattaaatat gatgaaaacg gcaacccgtg gtcggcttac 36600 ggcggtgatt ttggcgatac gccgaacgat cgccagttct gtatgaacgg tctggtcttt 36660 gccgaccgca cgccgcatcc agcgctgacg gaagcaaaac accagcagca gtttttccag 36720 ttccgtttat ccgggcaaac catcgaagtg accagcgaat acctgttccg tcatagcgat 36780 aacgagctcc tgcactggat ggtggcgctg gatggtaagc cgctggcaag cggtgaagtg 36840 cctctggatg tcgctccaca aggtaaacag ttgattgaac tgcctgaact accgcagccg 36900 gagagcgccg ggcaactctg gctcacagta cgcgtagtgc aaccgaacgc gaccgcatgg 36960 tcagaagccg ggcacatcag cgcctggcag cagtggcgtc tggcggaaaa cctcagtgtg 37020 acgctccccg ccgcgtccca cgccatcccg catctgacca ccagcgaaat ggatttttgc 37080 atcgagctgg gtaataagcg ttggcaattt aaccgccagt caggctttct ttcacagatg 37140 tggattggcg ataaaaaaca actgctgacg ccgctgcgcg atcagttcac ccgtgcaccg 37200 ctggataacg acattggcgt aagtgaagcg acccgcattg accctaacgc ctgggtcgaa 37260 cgctggaagg cggcgggcca ttaccaggcc gaagcagcgt tgttgcagtg cacggcagat 37320 acacttgctg atgcggtgct gattacgacc gctcacgcgt ggcagcatca ggggaaaacc 37380 ttatttatca gccggaaaac ctaccggatt gatggtagtg gtcaaatggc gattaccgtt 37440 gatgttgaag tggcgagcga tacaccgcat ccggcgcgga ttggcctgaa ctgccagctg 37500 gcgcaggtag cagagcgggt aaactggctc ggattagggc cgcaagaaaa ctatcccgac 37560 cgccttactg ccgcctgttt tgaccgctgg gatctgccat tgtcagacat gtataccccg 37620 tacgtcttcc cgagcgaaaa cggtctgcgc tgcgggacgc gcgaattgaa ttatggccca 37680 caccagtggc gcggcgactt ccagttcaac atcagccgct acagtcaaca gcaactgatg 37740 gaaaccagcc atcgccatct gctgcacgcg gaagaaggca catggctgaa tatcgacggt 37800 ttccatatgg ggattggtgg cgacgactcc tggagcccgt cagtatcggc ggaattccag 37860 ctgagcgccg gtcgctacca ttaccagttg gtctggtgtc aaaaataatt cgaaggcgaa 37920 agatcccaac gaaaagagag accacatggt ccttcttgag tttgtaacag ctgctgggat 37980 tacacatggc atggatgaac tgtacaactg aggatccccc gacctcgacc tctggctaat 38040 aaaggaaatt tattttcatt gcaatagtgt gttggaattt tttgtgtctc tcactcggaa 38 100 ggacatatgg gagggcaaat catttggtcg agatccctcg gagatcggat ctgggcgtgg 38 160 38160

Claims (2)

A trans-splicing group I ribozyme that is specifically recognizable by targeting Kras G12V RNA, AS100KRib2, represented by SEQ ID NO: 27. Anti-cancer pharmaceutical composition comprising ribozyme according to claim 1 as an active ingredient.

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